TW201811376A - Antibody-drug conjugates and therapeutic methods using the same - Google Patents

Abstract

The invention discloses an antibody-drug conjugate of Formula (I): (I)Ab-[L-Dn]xwherein: Abcomprises a broadly neutralizing anti-HIV antibody; Lcomprises a linker molecule covalently bonded to said broadly neutralizing anti-HIV antibody; Dcomprises one or more drugs comprising an HIV therapeutic compound covalently bonded to said linker molecule L, wherein said one or more broadly neutralizing anti-HIV antibodies Ab specifically bind to an HIV envelope glycoprotein and said one or more drugs D specifically bind to an HIV envelope glycoprotein; n is selected from 1-4; and x is selected from 1-12.

Description

Antibody-drug conjugate and treatment method using the same

The present invention relates to antibody-drug conjugates, pharmaceutical compositions and methods for individuals infected with HIV.

Human immunodeficiency viruses (HIV types 1 and 2) cause acquired immunodeficiency diseases (AIDS). Unfortunately, the number of HIV cases continues to rise, and more than 25 million individuals worldwide currently have the virus. At present, the long-term inhibition of viral replication with antiretroviral drugs is the only option for the treatment of HIV infection. In fact, the U.S. Food and Drug Administration (U.S. Food and Drug Administration) has approved 25 drugs in 6 different inhibitor classes, and these drugs have been shown to greatly improve patient survival and quality of life. However, due to various problems including (but not limited to) the following, other therapies are still needed: undesired drug-drug interactions; drug-food interactions; non-compliance with therapies; drug resistance caused by viral target mutations ; And inflammation associated with immune damage caused by HIV infection. Currently, almost all HIV-positive patients are treated with a combination of antiretroviral drugs called highly active antiretroviral therapy ("HAART"). However, HAART therapy is often complicated because it is often necessary to administer a combination of different drugs to patients daily to avoid rapid emergence of drug-resistant HIV variants. Although HAART has a positive effect on patient survival, drug resistance may still occur and the quality of life may not be normal compared to uninfected people [Lohse Ann Intern Med 2007 146; 87-95]. In fact, the incidence of several non-AIDS morbidities and deaths (such as cardiovascular disease, frailty, and neurocognitive disorders) has increased in HIV-infected patients suppressed by HAART [Deeks Annu Rev Med 2011; 62: 141-155 ]. This increased incidence of non-AIDS morbidity / death occurs in the context of increased systemic inflammation associated with immune damage caused by HIV infection and may be caused by it [Hunt J Infect Dis 2014] [Byakagwa J Infect Dis 2014] [Tenorio J Infect Dis 2014]. Although modern antiretroviral therapy (ART) can effectively inhibit HIV replication and improve the health status of HIV-infected persons, it is believed that it cannot completely remove the HIV virus pool in individuals. The HIV genome can be lurking in most immune cells in infected individuals and can be reactivated at any time, so that after ART is interrupted, viral replication usually resumes within a few weeks. In a few individuals, the size of this virus library has been significantly reduced and the rebound of virus replication has been delayed when ART is stopped [Henrich TJ J Infect Dis 2013] [Henrich TJ Ann Intern Med 2014]. In one case, the virus bank was eliminated during leukemia treatment and no viral rebound was observed during several years of follow-up [Hutter G N Engl J Med 2009]. These examples demonstrate the concept of reducing or eliminating the possibility of virus pools and alleviating or curing viruses. Thus, methods for eliminating the virus bank have been implemented by direct molecular means, including the use of the CRISPR / Cas9 system to excise the viral genome, or inducing reactivation of the latent bank during ART to eliminate the latent cells. The induction of latent pools usually results in the direct death of latently infected cells or killing the induced cells by the immune system after making the virus visible. When this induction is performed during ART, the virus genome produced by Xianxin will not infect new cells and the pool size may be attenuated. Even if HAART succeeds, the virus eventually develops drug resistance over time, making future ART always needed. In addition to exogenous treatment of HIV, the immune system also produces antibodies to HIV during the infection process, mainly targeting the HIV envelope protein gp160. These antibodies bind to virus particles and neutralize the ability of the virus particles to infect other target cells. The latest technology has provided a platform for separating neutralizing antibodies from infected individuals and over time has found better antibodies that neutralize different sequences of gp160. Explore various broad-spectrum neutralizing antibodies (bNAb) as ART by infusion into HIV-infected individuals or related models. Such bnAbs can also solve problems such as patient compliance, due to a longer circulating half-life compared to historical ART small molecules and can result in a dosing regimen once a month or even longer. In light of the above, there is a continuing need in this technology to develop other treatments for treating HIV-infected individuals and addressing such issues as patient compliance and potential reduction in ART dosing frequency. In addition, improvement measures targeting gp160 are needed in an attempt to increase the breadth of gp160 diversity that is inhibited and improve durability by providing multiple antiviral targets in a reagent similar to HAART provided by multiple small molecules.

In one aspect, the invention provides an antibody-drug conjugate of formula (I): Ab-LD (I) wherein: Ab contains a broad-spectrum neutralizing antibody; L contains a covalent bond to the The linker molecule of the broad-spectrum neutralizing antibody; and D includes one or more drugs covalently bonded to the linker molecule, and the one or more drugs specifically bind to the HIV envelope glycoprotein. In another aspect, the present invention provides an antibody-drug conjugate of formula (II): (II) Ab- [LD _n ] _x where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a covalent bond Linker molecules that neutralize anti-HIV antibodies in the broad spectrum; D contains one or more drugs, the one or more drugs include HIV attachment inhibitor compounds, covalently bonded to the linker molecules, wherein the one or more broad spectrum The neutralizing anti-HIV antibody specifically binds to the HIV envelope glycoprotein; n is selected from 1 to 4; and x is selected from 1 to 12. Also provided are pharmaceutical compositions comprising antibody-drug conjugates of formula (I) and formula (II) and methods of treating HIV-infected patients with antibody-drug conjugates of (I) and formula (II). The present invention covers these and other aspects as set forth herein.

This application claims the priority of the US provisional patent application serial number 62 / 357,410 filed on July 1, 2016. The content of this application is incorporated herein by reference. In this application, several examples concerning compounds, compositions and methods are mentioned. The multiple embodiments are intended to provide various illustrative examples and should not be interpreted as a description of alternative species. On the contrary, it should be noted that the description of multiple embodiments provided herein may overlap in scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the invention. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention. In this specification and subsequent patent applications, a number of terms will be mentioned, and these terms should be defined to have the following meanings. All granted patents, published patent applications and other publications cited in this article are deemed to be incorporated by reference in their entirety. In one aspect, the invention provides an antibody-drug conjugate of formula (I):Ab-LD (I) Where: Ab contains a broad-spectrum neutralizing antibody; L contains a linker molecule covalently bonded to the broad-spectrum neutralizing antibody; and D contains one or more drugs covalently bonded to the linker molecule, wherein the one or Many drugs specifically bind to the HIV envelope glycoprotein. In another aspect, the present invention provides an antibody-drug conjugate of formula (II):Ab- [L-D_n ]_x (II) Where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a linker molecule covalently bonded to the broad-spectrum neutralizing anti-HIV antibody; D contains one or more drugs that contain HIV adhesion inhibitor compounds , Covalently bonded to the linker molecule, wherein the one or more broad-spectrum neutralizing anti-HIV antibodies specifically bind to the HIV envelope glycoprotein; n is selected from 1 to 4; and x is selected from 1 to 12. In yet another aspect, the present invention provides an antibody-drug conjugate of formula (II):Ab- [LD _n ] _x (II) Where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a linker molecule covalently bonded to the broad-spectrum neutralizing anti-HIV antibody; D contains one or more drugs that contain HIV adhesion inhibitor compounds , Covalently bonded to the linker molecule, wherein the one or more broad-spectrum neutralizing anti-HIV antibodies specifically bind to the HIV envelope glycoprotein; n is selected from 1 to 2; and x is selected from 2 to 4. In yet another aspect, the present invention provides an antibody-drug conjugate of formula (II):Ab- [L-D_n ]_x (II) Where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a linker molecule covalently bonded to the broad-spectrum neutralizing anti-HIV antibody; D contains one or more drugs that contain HIV adhesion inhibitor compounds , Covalently bonded to the linker molecule, wherein the one or more broad-spectrum neutralizing anti-HIV antibodies specifically bind to the HIV envelope glycoprotein; n is 1; and x is 2. In another aspect, the present invention provides an antibody-drug conjugate of formula (I):Ab-LD (I) Where: Ab contains a broad-spectrum neutralizing antibody with binding affinity to HIV envelope glycoprotein; L contains one or more linker molecules covalently bound to the broad-spectrum neutralizing antibody; and D contains covalently bound to the One or more drugs of one or more linker molecules, the one or more drugs can bind to the HIV envelope glycoprotein. In another aspect, the present invention provides an antibody-drug conjugate of formula (I):(I) Ab- [LD _n ] _x Where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a linker molecule covalently bonded to the broad-spectrum neutralizing anti-HIV antibody; D contains one or more drugs that contain HIV therapeutic compounds, total Valence bonded to the linker molecule L, wherein the one or more broad-spectrum neutralizing anti-HIV antibodies Ab specifically binds to the HIV envelope glycoprotein and the one or more drugs D specifically bind to the HIV envelope glycoprotein; n Is selected from 1 to 4; and x is selected from 1 to 12. Preferably, n is selected from 1 to 2; and x is selected from 2 to 4. More preferably, n is 1; and x is 1 or 2. In another aspect, the present invention provides an antibody-drug conjugate of formula (I): (I)Ab- [LD _n ] _x Where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a linker molecule covalently bonded to the broad-spectrum neutralizing anti-HIV antibody; D contains one or more drugs that contain HIV therapeutic compounds, total Valence bonded to the linker molecule L, wherein the one or more broad-spectrum neutralizing anti-HIV antibodies Ab specifically binds to the HIV envelope glycoprotein and the one or more drugs D specifically bind to the HIV envelope glycoprotein; n Selected from 1 to 4; x is selected from 1 to 12, wherein the antibody-drug conjugate comprises (1) the first drug D is covalently bonded to the first linker molecule L, and the first linker molecule L is covalently bonded Bound to the broad-spectrum neutralizing antibody; and (2) the second drug D is covalently bound to the second linker molecule L, and the second linker molecule L is covalently bound to the broad-spectrum neutralizing antibody. In one embodiment, the first drug D is the same as the second drug D. In one embodiment, the first drug D is different from the second drug D. In one embodiment, the first linker and the second linker may be the same or different. In one embodiment, the first drug and the first linker are attached to the broad-spectrum neutralizing antibody at a different location than the second drug and the second linker. "Antibody" is defined as a polypeptide or fragment thereof that includes at least the light chain or heavy chain immunoglobulin variable region of an epitope that specifically recognizes and binds an antigen. Antibodies are composed of heavy and light chains, and each of these chains has a variable region, called a variable heavy chain (V_H ) Region and variable light chain (V_L )Area. V_H District and V_L Together, the region is responsible for binding the antigen recognized by the antibody. The term antibody includes intact immunoglobulins, as well as variants and parts thereof, such as single variable domains (eg, VH, VHH, VL, domain antibodies (DAB)); Fab fragments; F (ab) '₂ Fragment; single-chain Fv protein ("scFv"); disulfide-stabilized Fv protein ("dsFv"); bifunctional antibody; TANDABS, etc. and modified versions of any of the foregoing The scFv protein is a fusion protein in which the light chain variable region of the immunoglobulin and the heavy chain variable region of the immunoglobulin are bound by a linker, and within the dsFv, the chain has been mutated to introduce disulfide bonds to stabilize the association of the chain Together. The term also includes genetically engineered forms, such as chimeric antibodies (eg, humanized murine antibodies), hetero-binding antibodies (such as bispecific antibodies). See also,Pierce Catalog and Handbook , 1994-1995 (Pierce Chemical Co., Rockford, IL); Kuby, J.,Immunology , 3rd edition, W.H. Freeman & Co., New York, 1997. The term "single variable domain" refers to a folded polypeptide domain that contains sequences that characterize the variable domain of an antibody. It therefore includes intact antibody variable domains, such as VH, VHH, and VL; and modified antibody variable domains, such as where one or more loops have been replaced by sequences that do not characterize the antibody variable domain, or have been truncated or included N-terminal or C-terminal extended antibody variable domains, and folded fragments of variable domains that retain at least the binding activity and specificity of the full-length domain. A single variable domain can bind an antigen or epitope independently of different variable regions or domains. "Domain antibody" or "DAB" can be regarded as the same as "single variable domain". The single variable domain may be a human single variable domain, but also includes single variable domains from other species, such as rodent nurse sharks and camelids VHH DABS. Camelidae VHH is an immunoglobulin single variable domain polypeptide derived from species including camel, llama, alpaca, dromedary, and maroon llama, which produces heavy chain antibodies that are naturally free of light chains. Such VHH domains can be humanized according to standard techniques available in this technology, and such structural domains are considered "single variable domains." As used herein, VH includes the Camelidae VHH domain. Generally, naturally occurring immunoglobulins have heavy (H) chains and light (L) chains interconnected by disulfide bonds. There are two types of light chains: Lamuda (λ) and Gaba (κ). Five main heavy chain categories (or isotypes) determine the functional activity of antibody molecules: IgM, IgD, IgG, IgA and IgE. Each heavy and light chain contains constant and variable regions (these regions are also called "domains"). In combination, the heavy and light chain variable regions specifically bind antigen. The light chain and heavy chain variable regions contain a "framework" region interspersed with three hypervariable regions, also known as "complementarity determining regions" or "CDRs." The framework and CDR have been defined (see Kabat et al.,Sequences of Proteins of Immunological Interest , U.S. Department of Health and Human Services, 1991). The Kabat database is now maintained online. The sequences of the framework regions of different light or heavy chains are relatively preserved within the species. The framework region of an antibody-that is, the combined framework region constituting the light chain and the heavy chain is used to position and arrange the CDRs in three-dimensional space. The CDR is mainly responsible for binding to the epitope of the antigen. The CDRs of each chain are commonly referred to as CDR1, CDR2, and CDR3 (continuous numbering from the N-terminus), and are usually identified by the chain in which the specific CDR is located. Therefore, V_H CDR3 (also known as CDRH3) is located in the V_H CDR3 CDR3 in the variable domain of the antibody heavy chain, and V_L CDR1 (also known as CDRL1) comes from the discovery of the V_L CDR1 is the CDR1 of the variable domain of the antibody light chain. Antibodies that bind the target protein will have a specific V_H District and V_L Region sequences, and therefore have specific CDR sequences. Antibodies with different specificities (such as different combination sites of different antigens) have different CDRs. Although the CDR differs from antibody to antibody, only a limited number of amino acid positions within the CDR directly participate in antigen binding. These positions within the CDR are called specificity determining residues (SDR). In the present specification, the amino acid residues in the variable domain sequence and the full-length antibody sequence are numbered according to Kabat numbering convention. Similarly, unless otherwise indicated, the terms "CDR", "CDRL1", "CDRL2", "CDRL3", "CDRH1", "CDRH2", "CDRH3" follow the Kabat numbering convention. Those skilled in the art will understand that there are alternative numbering conventions for amino acid residues within variable domain sequences and full-length antibody sequences. Alternative numbering conventions for CDR sequences also exist, such as those stated in Chothia et al. (1989) Nature 342: 877-883. The structure of the antibody and protein folding may mean that other residues are considered part of the CDR sequence and the skilled person will understand so. Other numbering conventions for CDR sequences available to technicians include the "AbM" (University of Bath) and "Contact" (University College London) methods. It can be determined that the smallest overlap area using at least two of Kabat, Chothia, AbM, and contact methods is provided to provide a "minimal bonding unit." The smallest binding unit may be a sub-portion of the CDR. Table 1 below shows one definition of using each numbering convention for each CDR or binding unit. The Kabat numbering scheme is used in Table 1 to number the variable domain amino acid sequences. It should be noted that certain CDR definitions may vary depending on the individual disclosures used.table 1 "V_H "" Or "VH" refers to the variable region of the immunoglobulin heavy chain, including the variable region of Fv, scFv, dsFv or Fab. "V_L "" Or "VL" refers to the variable region of the immunoglobulin light chain, including the variable region of Fv, scFv, dsFv or Fab. If the following behavior can distinguish an antigen from one or more reference antigens, the antibody or other active agent "(eg specific) binds" to the antigen, "is specific" to the antigen or (eg specific) "recognizes" the antigen, This is because the binding specificity is not an absolute characteristic, but a relative characteristic. In its most common form (and when not referring to a defined reference), "binding" refers to the ability of an antibody or active agent to distinguish an antigen of interest from an unrelated antigen, as determined, for example, according to one of the following methods . Such methods include (but are not limited to) Western blot, ELISA test, RIA test, ECL test, IRMA test and peptide scanning. Scoring can be performed by standard color development (for example, secondary antibody containing horseradish peroxide and tetramethylbenzidine containing hydrogen peroxide). The response in some wells is scored by optical density (for example at 450 nm). The typical background (= negative reaction) can be 0.1 OD; the typical positive reaction can be 1 OD. This means that the positive / negative difference can exceed 10 times. Generally, instead of using a single reference antigen, a set of about three to five unrelated antigens (such as milk powder, BSA, transferrin, or the like) are used to determine the binding specificity. In addition, "binding" and more specifically "specific binding" may refer to the ability of an antibody to distinguish a target antigen from one or more closely related antigens (used as a reference point). In addition, "binding" can refer to the ability of an antibody to distinguish between different parts (eg different domains or regions) of its target antigen or one or more key amino acid residues or fragments of amino acid residues. "Affinity" or "binding affinity" refers to the total strength of non-covalent interactions between a single binding site (eg, antibody or molecule) of an active agent and its binding partner (eg, antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to an inherent binding affinity that reflects a 1: 1 interaction between members of a binding pair (eg, antibody and antigen). Affinity can be measured by common methods known in the art, including equilibrium methods (such as enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)) or kinetics (such as BIACORE analysis). A specific method for measuring affinity is surface plasmon resonance (SPR). For example, with regard to the term "binding affinity", an antibody that preferentially binds to a specific target protein (such as gpl20 or gp160) under specified conditions and does not bind to a large amount of other proteins or polysaccharides present in a sample or subject is called specific Antibody that binds sexually to its target. In one embodiment, the affinity is calculated by a modification of the Scatchard method described by Frankel et al., Mol. Immunol., 16: 101-106, 1979. In another embodiment, the binding affinity is measured by the antigen / antibody dissociation rate. In yet another embodiment, the binding affinity is measured by competitive radioimmunoassay. In several examples, the high binding affinity may be around 1 × 10^-6 M to about 1 × 10^-12 M, and more preferably about 1 × 10^-8 M to about 1 × 10^-12 Within M range. (10 nM to 1 pM) (see for example WO 2012/106578). "Affinity" is, for example, the sum of the strengths at which two molecules bind to each other at multiple sites when considering the valence of interaction. The "percent identity" between the query nucleic acid sequence and the target nucleic acid sequence is the "identity" value expressed as a percentage, which is 100% query coverage of the target nucleic acid sequence and the query nucleic acid sequence after pairwise BLASTN The rate is calculated by the BLASTN algorithm. Such pair-wise BLASTN alignment between the query nucleic acid sequence and the target nucleic acid sequence is performed by using the default settings of the BLASTN algorithm available on the National Center for Biotechnology Institute website and turning off the filter in the low complexity region. Importantly, the query nucleic acid sequence can be described by the nucleic acid sequence determined within the scope of one or more of the patent applications herein. The "percent identity" between the query amino acid sequence and the target amino acid sequence is the "consistency" value expressed as a percentage, which is the target amino acid sequence has the same The 100% query coverage of the acid sequence is calculated by the BLASTP algorithm. Querying this kind of pairwise BLASTP alignment between the amino acid sequence and the target amino acid sequence is by using the default settings of the BLASTP algorithm available on the National Center for Biotechnology Institute website and turning off the filtering of the low complexity area To carry out. Importantly, the query amino acid sequence can be described by the amino acid sequence determined within the scope of one or more patent applications in this document. The query sequence may be 100% identical to the target sequence, or it may include up to a certain integer number of amino acid or nucleotide changes compared to the target sequence so that the% identity is less than 100%. For example, the query sequence is at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% consistent with the target sequence. Such changes include at least one amino acid deletion, substitution (including conservative and non-conservative substitutions), or insertions, and these changes may occur between the amine terminal or carboxy terminal positions of the query sequence or between their terminal positions Anywhere, interspersed individually among amino acids or nucleotides within the query sequence or within one or more contiguous groups within the query sequence. The% identity can be determined over the entire query sequence length, including CDR. Alternatively, the% identity may not include the CDR, for example, the CDR is 100% identical to the target sequence and the% change in identity is within the remaining part of the query sequence, so that the CDR sequence is fixed / complete. The VH or VL sequence may be a variant sequence with up to 10 amino acid substitutions, additions or deletions. For example, the variant sequence may have up to 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitutions, additions or deletions. Sequence changes may not include CDRs, for example, CDRs are the same as VH or VL (or HC or LC) sequences and the changes are within the remainder of the VH or VL (or HC or LC) sequences, so that the CDR sequences are fixed / complete. In several embodiments, the constant region of the antibody includes one or more amino acid substitutions to optimize the in vivo half-life of the antibody. The serum half-life of IgG Ab can be regulated by nascent Fe receptor (FcRn). Therefore, in several embodiments, the antibody includes amino acid substitutions that increase binding to FcRn. Several such substitutions are known to those of ordinary skill, such as substitutions in the following regions of the IgG constant region: T250Q and M428L (see, for example, Hinton et al., J Immunol., 176: 346-356, 2006); M428L and N434S (" "LS" mutation, see for example Zalevsky et al., Nature Biotechnology, 28: 157-159, 2010); N434A (see eg Petkova et al., Int. Immunol., 18: 1759-1769, 2006); T307 A, E380A and N434A (See, eg, Petkova et al., Int. Immunol., 18: 1759-1769, 2006); and M252Y, S254T and T256E (see eg Dall 'Acqua et al., J. Biol. Chem., 281: 23514-23524, 2006 ). The disclosed antibodies may include Fc polypeptides that include any substitutions listed above, for example, Fc polypeptides may include M428L and N434. As discussed, the antibody according to the present invention may be adapted or modified to extend the serum half-life in vivo and thus make the functional activity of the antibody in the body last longer or longer. Appropriately, such modified molecules have reduced clearance and longer average residence time compared to unmodified molecules. The extended half-life can improve the pharmacokinetics and pharmacokinetic properties of the therapeutic molecule and is also essential for improving patient compliance. Other suitable half-life extension strategies include: PEGylation, polysialylation, hydroxyethyl starching, recombinant PEG mimetics, N-glycosylation, O-glycosylation, Fc fusion, engineered Fc, IgG binding, white Protein fusion, albumin binding, albumin coupling, and nanoparticles. Without intending to be bound by theory, it is reported that the long half-life of IgG antibodies depends on their binding to FcRn. Therefore, the constant region has been engineered to improve the binding affinity of IgG and FcRn at pH 6.0 while maintaining the pH-dependent substitution of the interaction (KUO, TT and AVESON, VG 2011. Neonatal Fc receptor and IgG-based therapeutics. MAbs, 3, 422-30). In adult mammals, FcRn (also known as nascent Fc receptors) can play a key role in maintaining serum antibody levels by acting as protective receptors that bind IgG isotype antibodies and rescue IgG isotype antibodies from degradation. IgG molecules are endocytosed by endothelial cells, and if they bind to FcRn, they are recycled into the circulation. In contrast, IgG molecules that are not bound to FcRn enter the cell and target the lysosomal pathway that degrades them. Xianxin's nascent FcRn receptor is involved in antibody clearance and transcytosis throughout the tissue (Kuo and Aveson, (2011)). Human IgG1 residues that can interact with human FcRn include Ile253, Ser254, Lys288, Thr307, Gln311, Asn434, and His435. The exchange at any of these positions described in this section can increase the serum half-life of the antibody of the invention and / or change its effect characteristics. Antibodies suitable for use in the methods of the invention as described herein can have amino acid modifications that can increase the affinity of the constant domain of FcRn or fragments thereof. Extending the half-life of therapeutic and diagnostic IgG polypeptides and other biologically active molecules can provide benefits including, for example, reducing the amount and / or frequency of administration of such molecules. In one embodiment, an antibody of the invention is therefore provided, which comprises all or part of an IgG constant domain modified with one or more amino acids (FcRn binding portion). Various methods are known to prolong half-life (Kuo and Aveson, (2011)), including amines produced by techniques including alanine scanning mutation induction, random mutation induction and screening to assess binding to FcRn and / or in vivo behavior Base acid modification. Computational strategies after mutation induction can also be used to select an amino acid mutation for mutation. Although substitutions in the constant region can improve the function of therapeutic IgG antibodies, substitutions in strictly conserved constant regions may have the potential risk of immunogenicity in humans, while substitutions in highly diverse variable region sequences The immunogenicity may be less. Reports related to variable regions include engineering CDR residues to improve binding affinity to antigens and engineering CDR and framework residues to improve stability and reduce the risk of immunogenicity. Improving affinity with antigens can be achieved by affinity maturation, using random phage or ribosome display. It is possible to obtain improved stability from rational design based on sequence and structure. Reducing the risk of immunogenicity (deimmunization) can be achieved by various humanization methods and removal of T cell epitopes. The risk of immunogenicity can be predicted using electronic hybridization techniques or determined by in vitro analysis. In addition, the variable area has been engineered to reduce pi. Compared to wild-type antibodies, despite comparable FcRn binding, these antibodies were observed to have a longer half-life. If the antigen-mediated clearance mechanism normally degrades the antibody when it binds to the antigen, engineer or select an antibody with pH-dependent antigen binding to modify the antibody and / or antigen half-life, for example, to shorten the IgG2 antibody half-life. Similarly, the antigen: antibody complex can affect the half-life of the antigen, extending the half-life by protecting the antigen from the typical degradation process or shortening the half-life by means of antibody-mediated degradation. Xian understands that in the production of antibodies, depending on the particular amino acid sequence of the cell line used and the antigen binding protein, post-translational modifications can be made. For example, this may include the cleavage of certain leader sequences, the addition of different sugar moieties in various glycosylation and phosphorylation modes, deamidation, oxidation, disulfide bond disruption, isomerization, C-terminal amine acid cleavage Shear and N-terminal glutamic acid cyclization. The invention encompasses the use of antigen binding proteins that have been subjected to or undergo one or more post-translational modifications. Accordingly, "antibodies" of the present invention include "antibodies" as previously defined that have undergone post-translational modification such as described herein. Deamidation system mainly converts asparagine (N) to isoaspartate (isoaspartate) and aspartate (aspartate) (D) at a ratio of about 3: 1 Enzyme reaction. Therefore, this deamidation reaction is related to the isomerization of aspartate (D) to isoaspartate. Both the deamidation of asparagine and the isomerization of aspartate involve the intermediate product succinimide. The glutamic acid residues can be deamidated in a similar manner to a much lower degree. Deamidation can occur in CDR, Fab (non-CDR regions) or Fc regions. Oxidation can occur during production and storage (ie, in the presence of oxidizing conditions) and leads to covalent modification of proteins, either directly induced by reactive oxygen species or indirectly induced by reaction with secondary byproducts of oxidative stress. Oxidation mainly occurs at methionine residues, but can occur at tryptophan and free cysteine residues. Oxidation can occur in CDR, Fab (non-CDR regions) or Fc regions. Disturbance of disulfide bonds can occur during production and basic storage conditions. In some cases, disulfide bonds can be broken or erroneously formed, resulting in unpaired cysteine residues (-SH). These free (unpaired) sulfhydryl groups (-SH) can promote reorganization. N-terminal glutamic acid (Q) and glutamate (glutamate) (E) in the heavy and / or light chain may form pyruvate (pGlu) via cyclization. Most pGlu formation occurs in production bioreactors, but it can be formed in a non-enzymatic manner, depending on the pH and temperature of processing and storage conditions. Cyclization of the N-terminal Q or E is usually observed in natural human antibodies. C-terminal lysine cleavage is an enzymatic reaction catalyzed by carboxypeptidase, and it is usually observed in recombinant and natural human antibodies. Variants of this process include the removal of lysine from one or two heavy chains due to cellular enzymes from recombinant host cells. Administration to human subjects / patients may result in the removal of any remaining C-terminal lysine. "Linker" ("L") refers to a substance (such as a molecule) that binds an antibody to one or more drugs. The linker may be a cleavable linker or it may be a non-cleavable linker. The linker is preferably not cleavable. The non-cleavable linker keeps the drug attached to the antibody. Alternatively, for the purposes of the present invention, a linker may allow antibodies to be coupled, bound, joined, connected, tethered to one or more drugs, etc., for example. In other embodiments, the binding of the linker to antibodies and drugs is via covalent bonds. "Gp120" is defined as the envelope protein from HIV. This envelope protein was originally synthesized as a longer precursor protein of 845 to 870 amino acids in size, called gp160. gp160 is cleaved by cell proteases into gp120 and gp41. gp120 contains most of the exposed surface's external domain of the HIV envelope glycoprotein complex, and it is gp120 that binds to both the cellular CD4 receptor and the cellular chemokine receptor (such as CCR5). See, for example, US Patent Publication No. 20160009789. "Gp41" is defined as an HIV protein that contains a transmembrane domain and maintains a trimer configuration; it interacts with gp120 in a non-covalent manner. The envelope protein of HIV-1 was originally synthesized in size as a longer precursor protein of 845 to 870 amino acids, called gp160. gp160 forms a homotrimer and undergoes glycosylation in a Golgi apparatus. In vivo, it is subsequently cleaved by cellular proteases into gp120 and gp41. The amino acid sequence of one example of gp41 is described in GENBANK.RTM. incorporated by reference herein with accession number CAD20975 (available on October 16, 2009) (SEQ ID NO: 1). It should be understood that the sequence of gp41 may be different from the sequence given in GENBANK.RTM. Registration number CAD20975. gp41 contains a transmembrane domain and generally maintains a trimer configuration; it interacts with gp120 in a non-covalent manner. See, for example, US Patent Publication No. 20160009789 (gp120 vs. gp41). The term "gp160" refers to an envelope protein with a molecular weight of 160 kDa and containing different glycosylation sites. Gp160 acts as a precursor to both gp41 and gp120. For the purposes of the present invention, gp160 is a representative envelope glycoprotein, and HXB2D is a non-limiting example of an envelope sequence. For HXB2D, see for examplehttps://www.hiv.lanl.gov/content/sequence/HIV/REVIEWS/HXB2.html , The contents of which are incorporated by reference. The term "enveloped glycoprotein" or "glycoprotein" or "EnV" refers to an oligosaccharide chain (glycan) containing covalently attached to the side chain of a polypeptide and exposed on the surface of the HIV envelope. For the purpose of the present invention, after the antibody-drug conjugate is administered to an individual, the HIV gp160 envelope glycoprotein binds to the antibody-drug conjugate. In some embodiments, the HIV gp160 envelope glycoprotein is bound to the antibody portion of the antibody-drug conjugate. The term "broad-spectrum neutralizing antibody" (bNAb) is defined as inhibition of viral attachment and cell entry via binding to HIV envelope glycoproteins (Env) (eg gp160), as a non-limiting example, 50% inhibition of infection by more than 50% in vitro , 60%, 70%, 80%, 90%, 95%, 99% or more of the large group (more than 100) of HIV-1 enveloped pseudotyped virus and virus isolate antibodies. See, for example, U.S. Published Patent Application No. 20120121597. The term "drug" refers to a therapeutic agent for HIV, which encompasses, for example, a compound or larger molecule (eg, protein or peptide) capable of inducing a desired medical, therapeutic, or preventive effect against HIV when appropriately administered to an individual or cell. For example, in one embodiment, the antibody-drug conjugate comprises one or more peptides fused to the C-terminus of the heavy chain and / or light chain and the linker is 1 to 50 amino acids in length. For the purposes of the present invention, the one binding site targeted is the CD4 binding site. In various embodiments, the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein at the CD4 binding site. As defined herein, CD4 is a differentiation cluster factor 4 polypeptide; it is a T cell surface protein that mediates interaction with MHC class II molecules. CD4 is also used as the primary receptor site of HIV on cells during HIV-I infection. It is known that CD4 binds to gp120 of HIV. The known sequence of the CD4 precursor has a hydrophobic signal peptide, an extracellular region of about 370 amino acids, a highly hydrophobic extension that is significantly consistent with the transmembrane domain of the MHC class II β chain, and a highly charged cell of 40 residues Inner sequence (Maddon, Cell 42:93, 1985). The term "CD4" includes polypeptide molecules derived from CD4, including CD4 fragments, which are produced by chemical (eg, enzyme) digestion or genetic engineering. Such fragments may be one or more complete CD4 protein domains. The extracellular domain of CD4 consists of 4 consecutive immunoglobulin-like regions (D1, D2, D3, and D4, see Sakihama et al., Proc. Natl. Acad. Sci. 92: 6444, 1995; US Patent No. 6,117,655) , And amino acids 1 to 183 have been shown to participate in gp120 binding. For example, a binding molecule or binding domain derived from CD4 will include a sufficient portion of the CD4 protein to mediate the specific and functional interaction between the binding fragment and the natural or viral binding site of CD4. One such binding fragment includes both the D1 and D2 extracellular domains of CD4 (DID2 is also a fragment of soluble CD4 or sCD4 (which is composed of D1D2D3 and D4)), although smaller fragments can also provide similar specific and functional binding of CD4 . The gp120 binding site has been mapped to D1 of CD4. See, for example, US Published Patent Application No. 20120282264. In another embodiment, the invention includes antibodies that bind to HIV envelope glycoproteins at the gp120-gp41 interface. Such antibodies include (but are not limited to) antibodies selected from 8ANC195, 35O22 and PGT151. An example of 8ANC195 is described in US Publication No. 20150361160. An example of 35O22 is described in US Publication No. 20160022803. An example of PGT151 is described in US Publication No. 20150152167. In another embodiment, the invention includes antibodies that bind to the gp41 proximal membrane outer region (MPER), including (but not limited to) 4E10, 10E8, 2F5, and Z13e1. An example of 4E10 is described in US Publication No. 20160009789 . An example of 10E8 is described in PCT Publication No. WO2013070776. An example of 2F5 is described in US Publication No. 20150158934. An example of Z13e1 is described in US Publication No. 20120269821. One of the better anti-system 10E8 in this group. Preferred antibodies for binding to HIV envelope glycoproteins include (but are not limited to) VRC01, VRC07, VRC07-523, 3BNC117, NIH45-46, PGV04, b12, CH31, and CH103. In other embodiments, preferred antibodies include, but are not limited to, VRC01, VRC01-LS, VRC07, VRC07-LS, VRC07-523, 3BNC117, NIH45-46, PGV04, b12, CH31, CH103, N6, and N6-LS. An especially preferred anti-system VRC01. An example of this VRC01 was disclosed in Zhou et al., "Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01",Science Express , July 8, 2010, pages 1-102,www.sciencemag.org /cgi/content/full/science.1192819/DC1. More specifically, VRC01 can be combined with gp120. VRC01 can neutralize 90% of HIV strains / subtypes. Another example of such an antibody that binds to gp120 is VRC01-LS, as disclosed in WO2012106578. Another example of such an antibody that binds to gp120 is VRC07, as disclosed in WO2013086533. One example of VRC07-523 is described in J. Virol, 88 (21): pages 12669-12682 (November 2014). An example of 3BNC117 is described in US Publication No. 20140212458. An example of NIH45-46 is described in US Publication No. 20150274813. An example of PGV04 is described in US Publication No. 20130251726. An example of b12 is described in US Publication No. 20160009789. An example of CH31 is described in US Publication No. 20130251726. An example of CH103 is described in US Publication No. 20140212458. In various embodiments, the broad-spectrum neutralizing antibody Ab is selected from the group consisting of: 2G12, 2F5, 3BC176, 3BNC60, 3BNC117, 4E10, 8ANC131, 8ANC195, 10E8, 10-1074, 12A12, 35O22, b12, B2530, CH01-04, CH103, CH31, HJ16, M66.6, N6, N6-LS, NIH45-46, PG9, PG16, PGDM1400, PGT121, PGT128, PGT135, PGT141-PGT145, PGT151, PGV04, VRC01, VRC01-LS, VRC07, VRC07-523, VRC07-LS and Z13. In view of the above, the resistance systems VRC01, VRC01-LS, N6, N6-LS, VRC07 and VRC07-523 are particularly preferred. In addition to the above, an example of the disclosure of VRC01 is also described in US Patent No. 8,637,036. An example of the disclosure of VRC01-LS is described in WO 2012/106578. Examples of the disclosure of N6 and N6-LS are described in WO 2016/196975. Examples of the disclosures of VRC07 and VRC07-523 are described in US Patent No. 8,637,036, US Patent Publication No. 2014/0322163 A1, WO 2016/196975 and WO2017 / 79479. In one embodiment, the broad-spectrum neutralizing antibody Ab binds to an HIV envelope glycoprotein selected from the group consisting of gp160, gp120, and gp41. In one embodiment, the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein gp120. In one embodiment, the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein gp41. In one aspect of the invention, the broad-spectrum neutralizing antibody comprises any one, two, three, four, five, or all of the following CDRs: CDRH1 (SEQ ID NO: 3), CDRH2 (SEQ ID NO : 4), CDRH3 (SEQ ID NO: 5), CDRL1 (SEQ ID NO: 6), CDRL2 (SEQ ID NO: 7) and CDRL3 (SEQ ID NO: 8). In one embodiment of the invention, the broad-spectrum neutralizing antibody comprises the heavy chain variable region of SEQ ID NO: 9 and / or the light chain variable region of SEQ ID NO: 10. In one embodiment of the invention, the broad-spectrum neutralizing antibody includes a leucine residue at position 428 of the heavy chain and a serine residue at position 434 of the heavy chain. In one embodiment of the invention, the broad-spectrum neutralizing antibody comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, SEQ ID NO: 11, 94%, 95%, 96%, 97%, 98%, 99% or 100% heavy chain with sequence identity and / or having at least 85%, 86%, 87%, 88%, 89 with SEQ ID NO: 13 Light chains with%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity. In one embodiment of the invention, the broad-spectrum neutralizing antibody comprises the heavy chain of SEQ ID NO: 12. In one embodiment, the broad-spectrum neutralizing antibody comprises a heavy chain having at least 90% sequence identity with SEQ ID NO: 9 and a light chain having at least 90% sequence identity with SEQ ID NO: 10. In one embodiment, the broad-spectrum neutralizing antibody comprises the heavy chain of SEQ ID NO: 11, optionally including the light chain of SEQ ID NO: 13. In one aspect of the invention, the broad-spectrum neutralizing antibody comprises any one, two, three, four, five, or all of the following CDRs: CDRH1 (SEQ ID NO: 14), CDRH2 (SEQ ID NO : 15), CDRH3 (SEQ ID NO: 16), CDRL1 (SEQ ID NO: 17), CDRL2 (SEQ ID NO: 18) and CDRL3 (SEQ ID NO: 19). In one embodiment, the broad-spectrum neutralizing antibody comprises a heavy chain having at least 90% sequence identity with SEQ ID NO: 20 and a light chain having at least 90% sequence identity with SEQ ID NO: 21. In one embodiment of the invention, the broad-spectrum neutralizing antibody comprises the heavy chain variable region of SEQ ID NO: 20 and the light chain variable region of SEQ ID NO: 21. In one embodiment of the invention, the broad-spectrum neutralizing antibody includes a leucine residue at position 428 of the heavy chain and a serine residue at position 434 of the heavy chain. In one embodiment of the invention, the broad-spectrum neutralizing antibody comprises at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% having SEQ ID NO: 22 , 94%, 95%, 96%, 97%, 98%, 99% or 100% of the heavy chain sequence identity and having at least 85%, 86%, 87%, 88%, 89% of SEQ ID NO: 23 , 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity of the light chain. According to the invention, the linker molecule is covalently bonded to a broad-spectrum neutralizing antibody. Examples of such linkers are known in the art and preferably include, for example, cleavable and non-cleavable linkers. Examples of non-cleavable linkers may include linkers containing polyethylene glycol chains or polyethylene chains that are insensitive to acids or bases (such as linkers containing hydrazones), linkers that are not sensitive to reducing agents or oxidizing agents (such as Disulfide bond linkers), and linkers that are insensitive to enzymes that can be found in cells or the circulatory system. See, for example, US Patent No. 8,470,980 and US Patent Application No. 20090202536. Examples of particularly preferred linkers include, but are not limited to, those linkers selected from the following structures. In these examples, the linker is described in the context of various antibody-drug conjugates of the invention. The chemical moiety indicated as "bNAb" represents a broad-spectrum neutralizing antibody to which each linker is bonded and is located at another position of the linker. Similarly, the term "drug" refers to an HIV attachment inhibitor compound to which each linker is bonded and is located at another position of the linker.Other examples of linkers include (but are not limited to) linkers as explained below:In the above embodiments, the bNAb and the drug are each attached to the linker via various bindings (eg, cysteine and lysine). Other suitable linkers can be used. Examples of particularly suitable linkers and methods of attachment to antibody-drug conjugates are disclosed in Perez et al., Drug Discovery Today, Volume 19, No. 7, (2014), pages 869-881. As explained therein, in one non-limiting example of chemical bonding, the reactive moiety attached to the drug-linker can be covalently attached to the side chain of the amino acid residue (usually the e-amine from the amino acid) antibody. As demonstrated by Mylotarg1, N-hydroxysuccinimide (NHS) esters attached to the drug-linker to form a stable amide bond can be used to bind the lysine residue directly to gemtuzumab (See for example Bros, PF et al., Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia,Clin. Cancer Res. , 17, pages 1490-1496 (2001). A two-step method can also be used, in which the surface lysine on the antibody is first modified to introduce a reactive group such as maleimide, and then bound to a drug containing a suitable reaction handle (eg thiol)- Linkers (see, for example, Junutula, JR et al., Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index, Nat. Biotechnol., 26: pages 925-932 (2008). Various known in the art Existing site-specific binding methods can be used to prepare ADCs. Such as thiomab drug binding, antibody drug conjugates via glutamine transaminase, non-natural amino acids for antibody drug conjugates, SmarTag [see for example Christopher R Behrens and Bin Liu, Methods for site-specific drug conjugation to antibodies, mAbs, Volume 6, Issue 1, pages 46-53 (2014)]. According to the present invention, antibody-drug conjugates include covalently bound to One or more drugs of the linker molecule, the one or more drugs can bind to the HIV envelope glycoprotein. As a non-limiting example, the one or more drugs are selected from attachment inhibitors. This also includes The following embodiment includes a first drug covalently bonded to a first linker molecule, the first linker molecule is covalently bonded to a bNAb; and a second drug covalently bonded to a second linker molecule , The second linker molecule is covalently bonded to bNAb. The term "attachment inhibitor" as used herein refers to a drug or agent used to treat HIV infection by interfering with HIV virion binding, fusion, and entry into human cells (Eg antiretroviral agents). Examples of attachment inhibitors include (but are not limited to) gp120 attachment inhibitors and gp160 attachment inhibitors. Examples of attachment inhibitors include (but not limited to) gp120 attachment inhibitors, gp160 attachment inhibitors And gp41 attachment inhibitors. Without intending to be bound by theory, in one embodiment, the attachment inhibitor targets the gp160 envelope protein (gp120 + gp41). An example of an attachment inhibitor is azaindole-side oxyethylpyrazine derivative And particularly preferred adhesion inhibitors have the following formula:, As described in US Patent Nos. 7,501,420; 7,354,924 and 7,662,823. Other examples of drugs include, but are not limited to, peptides (eg, as described in US Patent Nos. 6,133,418 and 6,475,491). For example, the drug may be a peptide that binds to CD4. A preferred example of this class of drugs is SEQ ID NO: 2 as set forth below: Ac-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln -Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH₂ SEQ ID NO: 2 is called T-20 and is commercially available from Roche under the trade name FUZEON®. Other examples of suitable compounds include, for example, the compounds described below: It is a gp160 adhesion inhibitor. The present invention also provides compounds of formula A that can be used as drugs in the antibody-drug conjugates disclosed herein:Where: X and Y are independently selected from the group consisting of: H, (C₁ -C₆ ) Alkyl, (C₁ -C₆ ) Alkoxy, halo, pendant, haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, dihaloalkoxy, trihaloalkoxy, hydroxyl, amine, amide And (C₁ -C₆ ) Alkyl- (C = O)-(C1-C6); R₁ , R₂ , R₃ , R₄ And R₅ Independently selected from H or (C₁ -C₆ ) Alkyl; m in the range of 0 to 5; more preferably in the range of 1 to 4; n in the range of 0 to 5; more preferably in the range of 1 to 4; r in the range of 0 to 6; more preferably 1 to 6, most preferably 1 to 4; p is 0 to 6, more preferably 1 to 6, most preferably 1 to 4; and q is 0 to 6, more preferably 1 to 6, most preferably 1 to 4 ; Wherein the compound of formula A can pass R₄ Or R₅ Or Y is attached to the linker. In one embodiment, regarding the formulaA Compound: X is selected from Cl and F; and m is 2; Y is H; R₁ , R₂ , R₃ , R₄ And R₅ Each is independently H; r is in the range of 1 to 4; best is 1; p is in the range of 1 to 4; best is 1; and q is in the range of 1 to 4; best is 2. A better formA The compound is:. Such compounds can be prepared according to the following synthesis:Where X, Y, m, n, R₁ And R₄ Defined above. Examples of drug-linker pairs that can be used in conjunction with the antibodies of the present invention include (but are not limited to) the following: andamong themIndicates attachment to bNAb. Specific examples of antibody-drug conjugates are as follows: Where t is in the range of 1 to 12. Examples of current compounds and agents used in the treatment of HIV include various other entry and fusion inhibitors, such as AMD070, BMS-488043, Fozivudine tidoxil, GSK-873,140 (aplaviroc), PRO 140, PRO 542, Peptide T, SCH-D (vicriviroc), TNX-355 and UK-427,857 (maraviroc); integrase inhibitors such as GS 9137, MK- 0518, as described in US Patent No. 9,259,433. In a non-limiting aspect, the invention encompasses antibody-drug conjugates in which the linker attaches the antibody to the agent by attaching to a specific amino acid within the antibody or antigen binding molecule. See, for example, US Patent No. 9,302,015. Exemplary amino acid attachments that can be used in the context of this aspect of the invention include, for example: lysine (see, eg, US Patent No. 5,208,020; US 2010/0129314; Hollander et al., Bioconjugate Chem., 2008, 19 : 358-361; WO 2005/089808; US Patent No. 5,714,586; US 2013/0101546; and US 2012/0585592), cysteine (see for example US 2007/0258987; WO 2013/055993; WO 2013/055990; WO 2013/053873; WO 2013/053872; WO 2011/130598; US 2013/0101546; and US Patent No. 7,750,116), selenium cysteine (see, for example, WO 2008/122039; and Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, 105: 12451-12456), methylglycine (see, for example, Carrico et al., Nat. Chem. Biol., 2007, 3: 321-322; Agarwal et al., Proc. Natl . Acad. Sci., USA, 2013, 110: 46-51, and Rabuka et al., Nat. Protocols, 2012, 10: 1052-1067), unnatural amino acids (see for example WO 2013/068874 and WO 2012 / 166559), and acidic amino acids (see for example WO 2012/05982). Linkers can also be attached to carbohydrates (see for example US 2008/0305497, WO 2014/065661 and Ryan et al., Food & Agriculture Immunol., 2001, 13: 127-130) and disulfide bond linkers (see for example WO 2013/085925, WO 2010/010324, WO 2011/018611 and Shaunak et al., Nat. Chem. Biol., 2006, 2: 312-313) bind to antigen binding proteins. In an embodiment in which the drug-based peptide or polypeptide (eg, DAB) within the antibody-drug conjugate, the linker may be a drug peptide or a drug peptide at one or two antibody heavy chains or one or two antibody light chains The drug polypeptide is linked to the antibody, thereby generating the amino acid linker of the fusion protein. In one embodiment, the drug peptide or drug polypeptide is fused to the C-terminus of one or both heavy chains of the antibody. In one embodiment, the length of the amino acid linker is between 0 and 150 amino acids, more specifically, in another embodiment, for example, between 0 and 50 amino acids. In another aspect, as defined herein, the invention encompasses antibody-drug conjugates in which one or more drugs are attached to the antibody at two or more discrete locations. This aspect may include, but is not limited to, any antibodies, linkers, and drugs as defined herein. Specific examples of such antibody-drug conjugates are (but not limited to):Where t and t 'are independently in the range of 1 to 12. "Cure" or "Curing" patients' disease is used to refer to the eradication, cessation, interruption or termination of human immunodeficiency virus or symptoms or the development of symptoms or viruses for a defined period of time. For example, in one embodiment, "Cure" or "Curing" means inducing and maintaining alone or in combination with one or more agents without any other therapeutic intervention for at least one year or two years, for example Durable virus control of human immunodeficiency virus (by, for example, polymerase chain reaction (PCR) test, bDNA (branch chain DNA) test or NASBA (nucleic acid sequence based amplification) test, the level of plasma viremia is undetectable) Therapeutic administration or combination of administration. The above PCR, bDNA and NASBA tests are performed using techniques known and familiar to those skilled in the art. For example, human immunity lacks viruses or symptoms or the eradication, cessation, interruption or termination of symptoms or virus development can be maintained for a minimum of two years. "Treating" or "treatment" of a patient's disease means 1) preventing the disease from happening to patients who are prone to disease or who have not yet shown symptoms of the disease; 2) inhibiting the disease or retarding its development; or 3) improving the disease or causing the disease Subside. According to an embodiment of the present invention, there is provided a pharmaceutical composition comprising the antibody-drug conjugate as described herein and a pharmaceutically acceptable excipient. According to one embodiment of the invention, there is provided a method of curing HIV infection in an individual, the method comprising administering to the individual an antibody-drug conjugate as described herein. According to an embodiment of the present invention, there is provided a method of curing HIV infection in an individual, the method comprising administering to the individual a pharmaceutical composition as described herein. According to an embodiment of the present invention, there is provided a method of treating HIV infection in an individual, the method comprising administering to the individual an antibody-drug conjugate as described herein. According to one embodiment of the present invention, there is provided a method of treating HIV infection in an individual, the method comprising administering to the individual a pharmaceutical composition as described herein. According to one embodiment of the present invention, there is provided a method of preventing HIV infection in an individual at risk of developing HIV infection, the method comprising administering to the individual an antibody-drug conjugate as described herein. According to an embodiment of the present invention, there is provided a method of preventing HIV infection in an individual at risk of developing HIV infection, the method comprising administering to the individual a pharmaceutical composition as described herein. In another embodiment of the present invention, there is provided an antibody-drug conjugate as described herein, which is used as a medicament. In another embodiment of the present invention, there is provided an antibody-drug conjugate as described herein, which is used to cure HIV infection. In another embodiment of the present invention, there is provided an antibody-drug conjugate as described herein for use in the treatment of HIV infection. In another embodiment of the present invention, there is provided an antibody-drug conjugate as described herein, which is used to prevent HIV infection. In another embodiment of the present invention, an antibody-drug conjugate is provided, wherein it is used to manufacture a medicament for treating HIV infection in humans. In another embodiment of the present invention, an antibody-drug conjugate is provided, wherein it is used to manufacture a medicament for preventing HIV infection in humans. In another embodiment of the present invention, an antibody-drug conjugate is provided, wherein the compound or salt thereof is used to manufacture a medicament for curing HIV infection in humans. In one embodiment, the pharmaceutical formulation containing the antibody-drug conjugate is suitable for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. The antibody-drug conjugate of the present invention can be used alone or in combination with other therapeutic agents. Therefore, in other embodiments, in addition to administering the antibody-drug conjugate, the method of treating and / or preventing HIV infection in an individual may further include administering one or more other agents that are active against HIV. In such embodiments, the one or more other agents having anti-HIV activity are selected from the group consisting of zidovudine, didanosine, lamivudine, Zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, and Todoxil, emtricitabine, alovudine, amdoxovir, amvuxitabine, nevirapine, delavirdine ), Efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC -278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprena Amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, substitute Tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355 , BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, raltegravir, elvitegravir, dolutegravir, cabotegravir, dimensional Vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, and Darunavir. Thus, the antibody-drug conjugate of the present invention and any other pharmaceutically active agent can be administered together or separately, and when administered separately, the administration can be performed simultaneously or continuously in any order. The amount and relative timing of administration of the antibody-drug conjugate and other pharmaceutically active agents of the present invention will be selected to achieve the desired combined therapeutic effect. The combination of antibody-drug conjugate and other therapeutic agents can be administered by the following concomitant administration: (1) a single pharmaceutical composition comprising two compounds; or (2) separate medicines each comprising one of the compounds combination. Alternatively, the combination can be administered separately in a sequential manner, where one therapeutic agent is administered first and another second therapeutic agent is administered second or vice versa. Such sequential casting can be close in time or very far apart in time. The amount and relative timing of antibody-drug conjugates and other pharmaceutically active agents will be selected to achieve the desired combined therapeutic effect. In addition, the antibody-drug conjugate can be used in combination with one or more other agents suitable for preventing, treating or curing HIV. Examples of such agents include:Nucleotide reverse transcriptase inhibitor , Such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adanfo, adefovir dipivoxil, fozivudine, todosi , Android, citabine, alovudine, amdoxovir, avtabine, TDF, TAF and similar agents;Non-nucleotide reverse transcriptase inhibitor (Including agents with antioxidant activity, such as imipracam, otepra, etc.), such as nevirapine, derivadine, efavirenz, loviramide, imicam, otepra, capraline , Le Sirini, GSK2248761, TMC-278, TMC-125, Etravirine and similar agents;Protease inhibitor , Such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fusanavir, becanavir, darunavir, atazanavir, tilanavir Wei, Palinavi, Lasinavir and similar agents;Integrase inhibitor , Such as rettevir, antegevir, bictegravir, duruvir, capravir and similar agents;Maturation inhibitor , Such as PA-344 and PA-457, and similar agents; and GSK2838232.CXCR4 and / or CCR5 Inhibitor , Such as Vic Viro (Sch-C), Sch-D, TAK779, Maravira (UK 427,857), TAK449, and disclosed in WO 02/74769, PCT / US03 / 39644, PCT / US03 / 39975, PCT / US03 / 39619, PCT / US03 / 39618, PCT / US03 / 39740 and PCT / US03 / 39732, among others, and similar agents. Other examples in which the antibody-drug conjugate of the present invention can be used in combination with one or more agents suitable for preventing or treating HIV are shown in Table 2.table 2 The scope of the combination of the antibody-drug conjugate and HIV agent of the present invention is not limited to those agents mentioned above, but in principle includes any combination with any pharmaceutical composition suitable for curing, treating and / or preventing HIV. As mentioned, in such combinations, the antibody-drug conjugates of the invention and other HIV agents can be administered separately or in combination. In addition, one agent may be administered before, concurrently with, or after other agents. The present invention can be used in combination with one or more agents suitable as pharmacological enhancers and with or without other compounds used to prevent or treat HIV. Examples of such pharmacological enhancers (or pharmacokinetic enhancers) include, but are not limited to, ritonavir, GS-9350, and SPI-452. Ritonavir [5S- (5S *, 8R *, 10R *, 11R *)] 10-hydroxy-2-methyl-5- (1-methylethyl) -1-1 [2- (1 -Methylethyl) -4-thiazolyl] -3,6-bi- pendant-8,11-bis (phenylmethyl) -2,4,7,12-tetraazatridecane-13 -Acid 5-thiazolyl methyl ester and available from Norvir from Abbott Laboratories of Abbott park, Illinois. Ritonavir is an HIV protease inhibitor indicated along with other antiretroviral agents used to treat HIV infection. Ritonavir also inhibits P450-mediated drug metabolism and P-glycoprotein (Pgp) cell transport system, thereby increasing the concentration of active compounds in the organism. GS-9350 is a compound developed by Gilead Sciences of Foster City California as a pharmacological enhancer. SPI-452 is a compound developed by Sequoia Pharmaceuticals of Gaithersburg, Maryland as a pharmacological enhancer. When used in combination with the chemical entities described herein, the other therapeutic agents described above can be used, for example, as indicated in the Physicians' Desk Reference (PDR) or in equivalent amounts as determined by those of ordinary skill in other ways. In another embodiment of the present invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses, the method comprising Or a mammal at risk of developing the virus infection is administered an antibody-drug conjugate. In another embodiment of the present invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses, the method comprising Or a mammal at risk of developing the virus infection is administered an antibody-drug conjugate, where the virus is an HIV virus. In some embodiments, the HIV virus is HIV-1 virus. In another embodiment of the present invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses, the method comprising Or a mammal at risk of developing the virus infection to administer the antibody-drug conjugate, the method further comprises administering a therapeutically effective amount of one or more agents having anti-HIV viral activity. In another embodiment of the present invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses, the method comprising Or a mammal at risk of developing the virus infection to administer an antibody-drug conjugate, the method further comprises administering a therapeutically effective amount of one or more agents with anti-HIV viral activity, wherein the agents with anti-HIV viral activity are selected Self-nucleotide reverse transcriptase inhibitors; non-nucleotide reverse transcriptase inhibitors; protease inhibitors; entry, attachment and fusion inhibitors; integrase inhibitors; maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors. In another embodiment of the present invention, there is provided a method for preventing a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses, the method comprising Or a mammal at risk of developing the virus infection is administered an antibody-drug conjugate. In another embodiment of the present invention, there is provided a method for preventing a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses, the method comprising Or a mammal at risk of developing the virus infection is administered an antibody-drug conjugate, where the virus is an HIV virus. In some embodiments, the HIV virus is HIV-1 virus. In another embodiment of the present invention, there is provided a method for preventing a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses, the method comprising Or a mammal at risk of developing the virus infection to administer the antibody-drug conjugate, the method further comprises administering a therapeutically effective amount of one or more agents having anti-HIV viral activity. In another embodiment of the invention, a method for curing a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses is provided, the method comprising Or a mammal at risk of developing the virus infection is administered an antibody-drug conjugate. In another embodiment of the invention, a method for curing a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses is provided, the method comprising Or a mammal at risk of developing the virus infection is administered an antibody-drug conjugate, where the virus is an HIV virus. In some embodiments, the HIV virus is HIV-1 virus. In another embodiment of the invention, a method for curing a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses is provided, the method comprising Or a mammal at risk of developing the virus infection to administer the antibody-drug conjugate, the method further comprises administering a therapeutically effective amount of one or more agents having anti-HIV viral activity. In another embodiment of the invention, a method for curing a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses is provided, the method comprising Or a mammal at risk of developing the virus infection to administer an antibody-drug conjugate, the method further comprises administering a therapeutically effective amount of one or more agents with anti-HIV viral activity, wherein the agents with anti-HIV viral activity are selected Self-nucleotide reverse transcriptase inhibitors; non-nucleotide reverse transcriptase inhibitors; protease inhibitors; entry, attachment and fusion inhibitors; integrase inhibitors; maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors. In another embodiment, a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of antibody-drug conjugate is provided. As used herein, the term "pharmaceutically acceptable" refers to those antibody-drugs that are suitable for contact with human and animal tissues without excessive toxicity, irritation, or other problems or complications, within the scope of reasonable medical judgment Conjugates, medicaments, compounds, materials, compositions and dosage forms. The drug administration described herein can be via any of the acceptable modes of administration that provide similarly effective agents, including (but not limited to): oral, sublingual, subcutaneous, intravenous, intranasal, topical, and Skin, intraperitoneal, intramuscular, lung, transvaginal, transrectal or intraocular. In some embodiments, oral or parenteral administration is used. An example of administration is intravenous administration. In this case, a pharmaceutical formulation suitable for intravenous administration is used. Another example of administration is intramuscular administration, in which case a pharmaceutical formulation suitable for intramuscular administration is used. Another example of administration is subcutaneous administration, in which case a pharmaceutical formulation suitable for subcutaneous administration is used. Pharmaceutical compositions or formulations include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, or similar dosage forms suitable for any of the above administrations. Antibody-drug conjugates can also be administered in sustained or controlled release dosage forms, including reservoir injections, osmotic pumps, pills, transdermal (including electromigration) patches, and similar dosage forms, for long-term and / Or timing pulse administration. In certain embodiments, the composition is provided in a unit dosage form suitable for single administration of precise dosages. The antibody-drug conjugates described herein can be used alone or more typically with conventional pharmaceutical carriers, excipients or analogs (e.g. mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, Cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate and the like) are administered in combination. If necessary, the pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers and the like (eg sodium acetate, sodium citrate, cyclodextrin derivatives, dehydrated sorbitan) Sugar alcohol monolaurate, triethanolamine acetate, triethanolamine oleate and the like). In general, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95% by weight; in certain embodiments, about 0.5% to 50% by weight ADC ?. The actual method of preparing these dosage forms is known, or will be apparent to those skilled in the art; for example seeRemington's Pharmaceutical Sciences , Mack Publishing Company, Easton, Pennsylvania. In certain embodiments, the composition will be in the form of pills or lozenges, and therefore along with the active ingredient, the composition will contain a diluent such as lactose, sucrose, dicalcium phosphate or the like; lubricants such as stearin Magnesium acid or its analogues; and binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives or their analogues. In another solid dosage form, the powder, marume, solution or suspension (for example in propyl carbonate, vegetable oil or triglyceride) is encapsulated in gelatin capsules. The liquid pharmaceutical composition can be administered, for example, by dissolving and dispersing at least one antibody-drug conjugate and optionally pharmaceutical adjuvant in a carrier (such as water, physiological saline, dextrose in water, glycerin , Glycol, ethanol or the like) is prepared to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or as solids suitable for solution or suspension in liquid prior to injection. The percentage of antibody-drug conjugates contained in such parenteral compositions is highly dependent on their specific properties and the activity of the chemical entity and the needs of the individual. However, a percentage of active ingredient in the solution of 0.01% to 10% is available, and it will be higher if the composition is a solid that is subsequently diluted to the above percentage. In certain embodiments, the composition will contain about 0.2% to 2% active agent in the solution. The pharmaceutical composition of the antibody-drug conjugate described herein may also be administered in the form of an aerosol or solution for nebulizers or in the form of fine powder for insufflation, alone or in combination with an inert carrier such as lactose Respiratory tract. In such cases, the diameter of the particles of the pharmaceutical composition is less than 50 microns, and in some embodiments less than 10 microns. In general, the provided antibody-drug conjugates are administered in a therapeutically effective amount by any of the acceptable modes of administration of agents that provide similar utility. The actual amount of antibody-drug conjugate depends on many factors, such as the severity of the disease to be treated, the age and relative health of the individual, the efficacy of the antibody-drug conjugate used, the route and form of administration, and others factor. The antibody-drug conjugate can be administered more than once a day, such as once or twice a day. The therapeutically effective amount of the antibody-drug conjugate described herein can be in the range of about 0.01 to 200 mg per kg of body weight of the recipient per day; such as about 0.01-100 mg / kg / day, for example about 0.01 to 50 mg / kg / day . Therefore, for administration to a 70 kg person, the dosage range may be about 1-1000 mg per day. Generally, antibody-drug conjugates are administered in the form of pharmaceutical compositions by any of the following routes: oral, systemic (eg, transdermal, intranasal, or suppository) or parenteral (eg, muscle) (Intravenously, intravenously or subcutaneously). In some embodiments, oral administration may be used, where the appropriate daily dosage regimen may be adjusted according to the degree of illness. The composition may take the form of lozenges, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. Another way to administer the provided chemical entities is by inhalation. The choice of formulation depends on various factors, such as the mode of drug administration and the bioavailability of antibody-drug conjugates. For delivery via inhalation, the chemical entity can be formulated as a liquid solution, suspension, aerosol propellant or dry powder and loaded into a suitable dispenser for administration. There are several types of medical inhalation devices-nebulizer inhalers, fixed dose inhalers (MDI) and dry powder inhalers (DPI). The nebulizer device generates a high-speed air flow, so that the therapeutic agent (dispensed into a liquid form) is sprayed into a mist and carried into the patient's respiratory tract. MDI is usually a compound encapsulated with compressed gas. Once activated, the device is a therapeutic agent that is measured by the amount of compressed gas released, thus providing a reliable method of administering a set amount of agent. DPI dispenses the therapeutic agent in the form of a free-flowing powder, which can be dispersed in the patient's inspiratory air flow by the device during breathing. To obtain a free-flowing powder, the therapeutic agent is formulated with excipients such as lactose. The measured therapeutic agent is stored in capsule form and dispensed with each actuation. Recently, pharmaceutical compositions have been developed for drugs that exhibit poor bioavailability based on the principle that bioavailability can be improved by increasing surface area (ie, decreasing particle size). For example, US Patent No. 4,107,288 describes pharmaceutical formulations with a particle size range of 10 to 1,000 nm, where the active substance is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which an API is pulverized into nanoparticles (average particle size is 400 nm) in the presence of a surface modifier, and then dispersed in a liquid medium to be demonstrated Significantly higher bioavailability of pharmaceutical formulations. The composition generally consists of at least one antibody-drug conjugate described herein in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic benefits of at least one chemical entity described herein. Such excipients can be any solid, liquid, semi-solid or (in the case of aerosol compositions) gaseous excipients generally available to those skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicone, magnesium stearate, sodium stearate, glyceryl monostearate, chlorine Sodium hydroxide, skimmed milk powder and the like. The liquid and semi-solid excipients can be selected from glycerin, propylene glycol, water, ethanol, and various oils including oils derived from petroleum, animal, plant, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Liquid carriers for injectable solutions include water, physiological saline, dextrose solution and glycol. Compressed gas can be used to disperse the antibody-drug conjugates described herein in aerosol form. Suitable inert gases for this purpose are nitrogen and carbon dioxide. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 18th edition, 1990). The amount of antibody-drug conjugate in the composition can vary within the full range used by those skilled in the art. Generally, in weight percent (wt%), the composition will contain about 0.01-99.99 wt% of the antibody-drug conjugate entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients. In certain embodiments, the antibody-drug conjugates described herein are present at a level of about 1-80 wt%. Various broad-spectrum neutralizing antibodies (bnAbs) have been explored as ARVs by infusion into HIV-infected individuals or related models, with limited success. The term "ARV" refers to "anti-retrovirus", which is a drug used to treat retrovirus (ie HIV) infection to inhibit the propagation of such viruses. Resistance to bnAb developed during treatment, similar to that observed with small molecule ARV. For this reason, it is believed that a bifunctional molecule composed of bnAb and a small molecule attachment inhibitor targeting gp160 according to the present invention can increase the breadth of the diversity of gp160 that is inhibited and by a molecule similar to HAART provided by multiple small molecules Provide a variety of anti-viral targets to improve durability. The term "HAART" refers to "highly active antiretroviral therapy", which is a combination of more than one (eg, 2, 3, or 4) drugs used to treat HIV.Examples 1 gp160 Synthesis of Attachment Inhibitor The following route is used to prepare the drug for the antibody-drug conjugate (Scheme 1) of the present invention: Examples 2 Experimental procedure Binding agentA To VRC01 and gp160 inhibitors and linkers were prepared according to Scheme 1 to Scheme 4. In this example, lysine binding is performed with VRCO1; therefore, succinimide ester is incorporated into the binding agent. As an alternative to trying to verify biological activity after all these modifications, compounds were also preparedB . Scenario 2Scheme 3Scheme 4Scheme 5Other binding methods such as cysteine binding and other site-specific binding methods can also be considered. With regard to these various combinations, suitable binding agents can be prepared accordingly using similar chemical schemes as described herein.Examples 3 gp160 Synthesis of Attachment Inhibitor The gp160 adhesion inhibitor is prepared according to the following synthetic route: N1- (4-((4- chlorine -3- Fluorophenyl ) Carbamoyl )-2-( Piperidine -1- Methyl ) Benzyl ) -N2- (3- ( Dimethylamino ) Propyl ) Ethylenediamide step 14- Nitro -3- ( Piperidine -1- Methyl ) Methyl benzoate Combine 3-methylaceto-4-nitrobenzoic acid methyl ester (15 g, 71.7 mmol) and piperidine (14.17 mL, 143 mmol) in 1,2-dichloroethane (DCE) (150 mL) The solution was treated with acetic acid (8.21 mL, 143 mmol). After 30 minutes, the reaction mixture was treated with sodium triethoxyborohydride (24.32 g, 115 mmol) and stirred overnight. Saturated NaHCO for reaction₃ Quenched, extracted with DCM, saturated NaHCO₃ , Brine washing, after Na₂ SO₄ Dry, filter and concentrate. The residue was purified by silica gel chromatography (EtOAc / hexane gradient) to give methyl 4-nitro-3- (1-piperidylmethyl) benzoate (16.14 g, 58.0 mmol, 81% yield) . LC / MS (m / z ) ES + = 279.3 (M + 1) + Step 2N- (4- chlorine -3- Fluorophenyl ) -4- Nitro -3- ( Piperidine -1- Methyl ) Benzamide A solution of methyl 4-nitro-3- (1-piperidylmethyl) benzoate (16.05 g, 57.7 mmol) in tetrahydrofuran (THF) (100 mL) and methanol (100 mL) was treated with LiOH (250 mL, 250 mmol) and stirred at ambient temperature for 4 hours. The mixture was concentrated to give the crude product 4-nitro-3- (1-piperidylmethyl) benzoic acid (20.51 g). Suspend the acid intermediate in SOCl₂ (50 mL, 685 mmol), refluxed for 1.5 hours, and concentrated to give 4-nitro-3- (1-piperidylmethyl) benzoyl chloride (LCMS, meoh, ES + 279, methyl ester) . The acetyl chloride was suspended in dichloromethane (DCM) (100 mL), using 4-chloro-3-fluoroaniline (7.97 g, 54.8 mmol), Et₃ Treated with N (12.06 mL, 87 mmol) and stirred at ambient temperature overnight. Also add Et₃ N (4 mL), DCM (11 mL) and aniline (418 mg), and the reaction was stirred overnight. Saturated NaHCO for suspension₃ Quenched, extracted twice with DCM, saturated NaHCO₃ Wash once, wash with brine, pass Na₂ SO₄ Dry, filter and concentrate. Purified by silica gel column chromatography (0-50% EtOAc / hexane) to obtain N- (4-chloro-3-fluorophenyl) -4-nitro-3- (1- Piperidinylmethyl) benzamide (13.86 g, 35.4 mmol, 61.3% yield). LC / MS (m / z ) ES + = 279.3 (M + 1) + Step 34- Amine -N- (4- chlorine -3- Fluorophenyl ) -3- ( Piperidine -1- Methyl ) Benzamide N- (4-chloro-3-fluorophenyl) -4-nitro-3- (1-piperidylmethyl) benzamide (13 g, 33.2 mmol) in methanol (130 mL) The solution was slowly added to a refluxing mixture of hydrazine hydrate (16.14 mL, 332 mmol) and Raney 2800 nickel (4.2 g, 33.2 mmol) in methanol (130 mL). The reaction was refluxed for 1 hour, cooled to ambient temperature, filtered through celite, washed with MeOH and DCM, and then concentrated to give the crude product 4-amino-N- (4-chloro-3-fluoro) as a pale yellow solid Phenyl) -3- (1-piperidinylmethyl) benzamide (11.56 g, 31.9 mmol, 96% yield). LC / MS (m / z ) ES + = 362.3 (M + 1) + Step 44- bromine -N- (4- chlorine -3- Fluorophenyl ) -3- ( Piperidine -1- Methyl ) Benzamide An ice-cooled mixture of copper (II) bromide (0.648 g, 2.90 mmol) in acetonitrile (20 mL) was treated with tert-butyl nitrite (0.730 mL, 5.53 mmol), followed by 4-amino-N- (4 -Chloro-3-fluorophenyl) -3- (1piperidylmethyl) benzamide (1.000 g, 2.76 mmol) and the resulting dark mixture was stirred at ambient temperature overnight. Add saturated NaHCO₃ And diluted with ethyl acetate. The mixture was filtered through a pad of diatomaceous earth and the aqueous layer was extracted with EA. The extract was washed with brine, washed with Na₂ SO₄ Dry, filter and concentrate. The residue was purified by silica gel chromatography (0-10% MeOH / DCM gradient) to give a dark residue (482 mg, 32%). 1H NMR (400 MHz, methanol-d4) d ppm 1.50 (d, J = 5.07 Hz, 2 H), 1.56-1.71 (m, 4 H), 2.53 (br. S., 4 H), 3.67 (s, 2 H), 7.37-7.48 (m, 2 H), 7.68-7.76 (m, 2 H), 7.78-7.87 (m, 1 H), 8.05 (d, J = 1.95 Hz, 1 H); LC / MS (m / z) ES + = 425 (M + 1). Step 5N- (4- chlorine -3- Fluorophenyl ) -4- Cyano -3- ( Piperidine -1- Methyl ) Benzamide Combine 4-bromo-N- (4-chloro-3-fluorophenyl) -3- (1-piperidinyl-methyl) benzamide (2 g, 4.70 mmol) and Zn (CN)₂ (0.386 g, 3.29 mmol) in N, N-dimethylformamide (DMF) (23.49 ml) was suspended with N₂ Degas for 5 minutes and then use Pd (PPh₃ )₄ (0.271 g, 0.235 mmol). The reaction mixture was irradiated in the microwave at 120 ° C for 20 minutes. The reaction mixture was poured into water and extracted with EtOAc. The combined extracts were washed with brine and dried (Na₂ SO₄ ), Filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc-hexane) to give N- (4-chloro-3-fluorophenyl) -4-cyano-3- (1-piperidinylmethyl ) Benzoamide (1.66 g, 4.46 mmol, 95% yield). LC / MS (m / z) ES + = 372.3 (M + 1). Step 64- ( Aminomethyl ) -N- (4- chlorine -3- Fluorophenyl ) -3- ( Piperidine -1- Methyl ) Benzamide Ammonia-saturated N- (4-chloro-3-fluorophenyl) -4-cyano-3- (1-piperidylmethyl) benzamide (5.00 g, 13.45 mmol) in ethanol (100 The mixture in mL) was treated with Raney 2800 nickel (12 mL, 13.45 mmol) and then stirred under 50 psi hydrogen for 72 h. The mixture was filtered on Celite and washed with ethyl acetate, DCM and MeOH. The filtrate was concentrated to give the title compound product as a light green solid.¹ H NMR (400 MHz, methanol-d4) d ppm 1.56 (br. S., 6 H), 2.48 (br. S., 4 H), 3.61 (s, 2 H), 3.90 (s, 2 H), 7.38-7.55 (m, 3 H), 7.76-7.90 (m, 3 H); LC / MS (m / z) ES + = 376 (M + 1). Step 72-((4-((4- chlorine -3- Fluorophenyl ) Carbamoyl )-2-( Piperidine -1- Methyl ) Benzyl ) Amine )-2- Pendant methyl acetate Combine 4- (aminomethyl) -N- (4-chloro-3-fluorophenyl) -3- (1-piperidinylmethyl) benzamide (1.000 g, 2.66 mmol) and Schunich's An ice-cooled mixture of Hunig's base (0.697 mL, 3.99 mmol) in tetrahydrofuran (THF) (20 mL) was slowly treated with methylethylenedichloride (0.270 mL, 2.93 mmol). The mixture was stirred for 5 minutes and was judged complete by LCMS. The mixture was diluted with ethyl acetate, followed by saturated NaHCO₃ And brine washing, after Na₂ SO₄ Dry, filter and concentrate. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to give the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d 6) d ppm 1.33-1.46 (m, 2 H), 1.46-1.57 (m, 4 H), 2.37 (br. S., 4 H), 3.57 (s, 2 H), 3.78 (s, 3 H) , 4.56 (d,J = 6.06 Hz, 2 H), 7.43 (d,J = 8.01 Hz, 1 H), 7.51-7.62 (m, 2 H), 7.80 (d,J = 1.56 Hz, 1 H), 7.85 (dd,J = 8.01, 1.76 Hz, 1 H), 7.91-7.97 (m, 1 H), 9.51 (t,J = 6.06 Hz, 1 H), 10.49 (s, 1 H); LC / MS (m / z ) ES + = 462 (M + 1). Step 82-((4-((4- chlorine -3- Fluorophenyl ) Carbamoyl )-2-( Piperidine -1- Methyl ) Benzyl ) Amine )-2- Pendant acetic acid 2-((4-((4-chloro-3-fluorophenyl) aminecarboxamide) -2- (piperidin-1-ylmethyl) benzyl) amino) -2-oxo A solution of methyl acetate (288 mg, 0.623 mmol) in MeOH (5 mL) and THF (5 mL) was treated with 1 M LiOH (1 mL). After 2 hours, the reaction mixture was concentrated in vacuo to give the title compound (279 mg, 106%). LC / MS (m / z ) ES + = 448.3 (M + 1). Step 9N1- (4-((4- chlorine -3- Fluorophenyl ) Carbamoyl )-2-( Piperidine -1- Methyl ) Benzyl ) -N2- (3- ( Dimethylamino ) Propyl ) Ethylenediamide ({[4-{[(4-chloro-3-fluorophenyl) amino] carbonyl] -2- (1-piperidinylmethyl) phenyl] methyl} amino) (side oxygen) Acetic acid (30.0 mg, 0.066 mmol), N, N-dimethyl-1,3-propanediamine (0.017 mL, 0.132 mmol) and Schunich's base (0.035 mL, 0.198 mmol) in N, N-di The mixture in methylformamide (DMF) (1.0 mL) was treated with T3P (0.079 mL, 0.132 mmol) and then stirred at ambient temperature for 5 minutes. The mixture was purified by RP-HPLC (TFA modification) to obtain the slightly impure desired product, which was further purified by RP-HPLC (NH4OH modification) to obtain the desired product as a white solid. 1H NMR (400 MHz, DMSO-d 6) d ppm 1.40 (br. S., 2 H), 1.49-1.64 (m, 6 H), 2.09 (s, 6 H), 2.18 (t,J = 7.02 Hz, 2 H), 2.37 (br. S., 4 H), 3.15 (q,J = 6.57 Hz, 2 H), 3.57 (s, 2 H), 4.52 (d,J = 6.24 Hz, 2 H), 7.42 (d,J = 7.80 Hz, 1 H), 7.52-7.66 (m, 2 H), 7.79 (s, 1 H), 7.84 (dd,J = 7.90, 1.46 Hz, 1 H), 7.89-8.00 (m, 1 H), 8.85 (t,J = 5.95 Hz, 1 H), 9.23-9.36 (m, 1 H), 10.48 (s, 1 H); LC / MS (m / z ) ES + = 532 (M + 1).Examples 4- Examples 8 antibody - Preparation of drug conjugates The antibody drug conjugate as described below was prepared as described below: Experimental material: VRC01 is expressed in CHO cells. The cell culture supernatant was collected and purified with protein A column and SEC column. The broad-spectrum neutralizing antibody VRC01 is stored in 20 mM histidine buffer (containing 5% sucrose, pH 6.0). Purity by size exclusion chromatography (SEC-HPLC , Figure 1 ) Analysis and electrophoresis of sodium lauryl sulfate polyacrylamide gel (SDS-PAGE , Figure 2 )to make sure.table 3 Four different payload-connectors used to combine (PL ) Designed and prepared as follows: Compound No. 1 (payload A, compoundLA ) Compound No. 2 (payload A, compoundSA ) Compound No. 3 (payload B, compoundSB ) Compound No. 4 (payload B, compoundLB ) among them:LA : Long connector payload ASA : Short connector payload ASB : Short connector payload BLB : Long connector payload B Analytical method HPLC method SEC analysis methodtable 4 The free drug analysis is described in Table 5, where the report is presented in Example 4.table 5 UV method for measuring DAR: UV / Vis and SEC (UV detector) based on Beer-Lambert Law A = E * c * l A280 = E ^mAb ₂₈₀ * [mAb] * l + E ^PL ₂₈₀ * [PL] * l A315 = E ^mAb ₃₁₅ * [mAb] * l + E ^PL ₃₁₅ * [PL] * l [mAb]: mAb concentration PL: payload-linker [PL]: payload-linker concentration E: molar extinction coefficient c: concentration l: optical path (Nanodrop: 0.1 cm)Examples 4 Chemical compoundSB A solution in dimethylacetamide (DMA, 10 mg / mL) was obtained by combining 1.2 mg of the compoundSB (Compound No. 3) was prepared by dissolving in 0.12 mL DMA. Chemical compoundLB The solution in DMA (10 mg / mL) was obtained by combining 2.1 mg of compoundLB (Compound No. 4) was prepared by dissolving in 0.21 mL DMA. Chemical compoundLA A solution in acetonitrile (ACN, 10 mg / mL)LA Prepared by dissolving in 0.17 mL ACN. Chemical compoundSA Solution in ACN (10 mg / mL) by combining 1.3 mg of compoundSA (Compound No. 2) was prepared by dissolving in 0.13 mL ACN. To determine the residence time of the payload-linker, the above preparedLA ,SA andLB , SB The solution is diluted with buffer (50% 100 mM NH₄ OAc + 50% acetonitrile) diluted to 1 mg / mL.LA ,SA andLB ,SB Both show two peaks (parent O-Su and hydrolyzed-COOH) within HPLC. The final antibody-drug conjugate (ADC) sample was submitted to HPLC (mixed mode RP column) to determine free payload-linker content. All ADC products had a clear peak at 3.3 min (antibody-related), and no other peaks appeared in the spectrum. The results showed that the remaining free payload-linker concentration in the ADC solution was below the detection limit. To determine the free payload-linker detection limit, prepare different concentrations ofLA ,SA andLB ,SB It was submitted to HPLC (mixed mode RP column), and the results showed that the detection limit of all four payload-linkers was less than 0.0024 μg / mL. Drug-antibody ratio (herein referred to as "DAR") MSExamples 5 Sample Preparation Add 100 μg protein sample to a 1.5 mL tube, so make up 100 μL with 2 μL 1 mol / L Tris-HCl buffer, 2.5 μL PNGase F solution and Milli-Q water. This was thoroughly mixed and incubated at 37 ° C for 4 hours. Using an ultrafiltration tube, 400 μL of 50 mM sodium phosphate buffer was added to the sample, followed by centrifugation at 13000 rpm for 15 minutes. The sample was then transferred to a 1.5 mL tube, and 50 mM sodium phosphate was added to a final volume of 100 μL. 1 μL of sialidase A and 2 μL of O-glycanase were added, and incubated at 37 ° C for 2 hours.table 6 HPLC conditions table 7 MS conditions Examples 6 VRC01-LA and VRC01-SA Preparation Response settings (LA and SA ): VRC01-LA and VRC01-SA, mentioned in Figure 3A and Figure 3B, respectively, to prepare VRC01-LA and VRC01-SA CH₃ CN was added to the VRC01 solution in PBS buffer (pH 7.5) and mixed to react, then CH was added₃ LA or SA solution in CN. After adding the payload-linker CH₃ The total content of CN in the binding solution is 20%. The reaction mixture was then placed in an electroshock (150 rpm) in a 22 ° C incubator for two hours. After two hours, the reaction mixture was removed and by using a rotary desalting column and amicon ultrafiltration (30 kDa), the buffer was replaced with storage buffer and the free payload-linker was removed. About 20-25 mg of final product was obtained and the reaction conversion rates were about 60% and 90%.table 8 * produce 30 mg VRC01-LA * produce 30 mgVRC01-SA Examples 7 VRC01-LB and VRC01-SB Preparation Response settings (LB , SB ) : VRC01-LB and VRC01-SB, mentioned in FIGS. 4A and 4B, respectively, DMA is added to the VRC01 solution in PBS buffer (pH 7.5), and the reaction is appropriately mixed, and then the LB or SB solution in DMA is added. After adding the payload-linker, the total content of DMA in the binding solution was 10%. The reaction mixture was then placed in an electroshock (150 rpm) in a 22 ° C incubator for two hours. After two hours, the reaction mixture was removed and by using a rotary desalting column, the buffer was changed to storage buffer and free drug was removed. About 20-25 mg of final product was obtained and the reaction conversion rates were about 70% and 80%.table 9 * Generate 25-30 mg VRC01-LB and SB; PL: payload-linker remove free payload-linker dialysis card (capacity 0.5-3 mL, MWCO: 10,000) total 4 ADC products (1.9 ml VRC01-SB, 2.1 mL VRC01-LB, 1.65 mL VRC01-LA and 1.15 mL VRC01-SA) were dialyzed 6 times with 500 mL buffer (20 mM histidine, pH 6.0) to remove the free payload-connection child. After dialysis, the concentration of ADC product, free drug content and endotoxin produced were determined by UV / Vis, HPLC (mixed mode RP column) and microplate reader. Then 5% sucrose was added to the ADC solution separately. The DAR and aggregate content of ADC products were determined by SEC-HPLC.table 10 Characteristics of all ADCs (no free payload detected-linker: <0.0024 μg / mL) Examples 8 Preparation of VRC01-LA-SB and VRC01-LA-LBResponse settings : The final structural products resulting from the following synthesis are mentioned in Figures 5A and 5B. CH₃ CN was added to VRC01 solution in PBS buffer (pH 7.5) and mixed to react, then CH was added₃ LA solution in CN. CH₃ The total content of CN in the binding solution was 20% and the final mAb concentration in the reaction was 10 mg / mL. After adding the payload-linker, the reaction mixture was then placed on a rotating platform (10 revolutions / minute) in an incubator at 22 ° C for two hours. The reaction mixture was then removed and the free payload-linker (LA) was removed by using amicon ultrafiltration (50 kDa). Approximately 2 mg of ADC was subjected to intact MS and SEC to measure DAR and aggregates. The remaining 18 mg of the reaction mixture was divided into two vials (9.0 mg each) and was subsequently combined with SB and LB, respectively. DMA and the SB and LB solutions in DMA were added to the ADC PBS buffer prepared above. The DMA content in the binding reaction was 20% and the ADC concentration was 10 mg / mL. The binding solution was placed on a rotating platform (10 revolutions / minute) inside a 22 ° C incubator for 2 h. The reaction mixture was then replaced with storage buffer by amicon ultrafiltration (50 kDa) with buffer and the free payload-linker was removed. Finally, the reaction mixture was dialyzed to further remove the free payload-linker to an undetectable level and the buffer was changed (3 days, 6 buffer changes). About 4.5 mg (each) of final product was obtained and the reaction conversion rate was about 50%.Such ADC Determination of free drug content in products : To determine the residence time of mAb and free payload-linker, use dilution buffer (50% 100 Mm NH₄ Ac + 50% acetonitrile) Dilute the solution of LA, LB and SB (all drug concentrations are 10 mg / mL) to 0.2 mg / mL. The payload-linker solution was then mixed with the mAb and the final drug concentration and mAb concentration in the sample were 0.1 mg / mL and 1 mg / mL, respectively. LA, LB and SB showed two peaks in HPLC (Supelco HISEP, 4.6 × 250 mm, 5 µm, CJ-00005105). When the mAb concentration in the sample was 1 mg / mL, no peak was displayed at 3.3 min. When the mAb concentration increased to 3 mg / mL, the corresponding peak was observed at 3.3 min, which indicates that the retention time of the mAb is 3.3 min. ADC samples were subjected to HPLC to determine free payload-linker content. The ADC product had a peak at 3.3 min, and no other peaks were observed, indicating that the free payload-linker concentration in the ADC solution was below the detection limit. To determine the detection limit, different concentrations of LA, LB, and SB were prepared and subjected to HPLC, and the results showed that the detection limits of LA, LB, and SB were all less than 0.006 µg / mL.table 11 Features of VRC01-LA-SB * The sample was subjected to de-N-glycosylation and de-O-glycosylation and then measured by MS to obtain MS DAR. * Storage buffer: 20 mM histidine, 5% sucrose, pH 6.0table 12 Features of VRC01-LA-LB * The sample was subjected to de-N-glycosylation and de-O-glycosylation and was measured by MS to obtain MS DAR. * Storage buffer: 20 mM histidine, 5% sucrose, pH 6.0Biological data program Pseudotype virus analysis (PSV) is used to analyze the efficacy of various HIV entry inhibitors. The replication-defective virus consists of a plastid containing the NL4-3 provirus [a luciferase reporter gene containing mutations in the open reading frame (ORF) of the envelope and replacing the nef ORF] and an ORF containing pure envelopes of various HIV gp160 The CMV-promoter is produced by plastid co-transfection. The collected virus was stored in small aliquots at -80 ° C and the titer of the virus was measured to generate a stable signal for antiviral analysis. PSV analysis was performed by using U373 cells as infection target cells, which were stably transformed to express human CD4 as a primary receptor for HIV entry, and human CXCR4 or human CCR5 as a co-receptor for HIV entry. The molecules of interest (including (but not limited to) HIV small molecule inhibitors, HIV neutralizing antibodies, HIV antibody-drug conjugate inhibitors, HIV peptide inhibitors, and various controls) are diluted in tissue culture media and passed Serial dilutions are used for dilution to produce concentrations in the dose range. This dose range is applied to U373 cells and pre-made pseudotyped virus is added. The amount of luciferase signal generated after 3 days of cultivation was used to reflect the level of pseudotyped virus infection. Calculate IC50 or the concentration of inhibitor required to reduce PSV infection by 50% from infection without inhibitor. At the same time, analysis for measuring cytotoxicity is performed to ensure that the observed antiviral activity of the inhibitor can be distinguished from the reduced viability of the target cells. Table 13 provides the results produced in the following Tables 14 to 16 and the materials mentioned in the drawings detailing the structure of each (i.e. drugs, linkers, antibodies, antibody-drug conjugates (`` ADC '')) .table 13 Table 14 provides the efficacy values of drugs and drug-linker materials.table 14 EFV is efavirenz. Table 15 provides various values of drugs, drug-linker materials, and ADC (single payload).table 15 Table 16 provides various values of drugs, drug-linker materials, and ADC (dual payload).table 16 The present invention is advantageous and contributes to this technology. By using ADC technology to tie Xianxin's bNAb with complementary virus coverage and small molecules targeting the envelope, wider virus coverage can be achieved. The pharmacokinetic properties of bNAb (preferably with a half-life extending mutation) can be advantageously used. Without being bound by theory, Xianxin uses a single bNAb of HIV treatment to affect the emergence of resistance. ADCs can possess multiple antiviral modes of action (MoA), all of which target the viral envelope, which can hinder the choice of escape variants and improve resistance patterns. Any cell / tissue other than virus has minimal undesired absorption of small molecules ARV tethered to bNAb, and this can improve its safety profile, tolerability and reduce the effective dose. In summary, the present invention is highly advantageous because antibody-drug conjugates act as bispecific molecules. More specifically, antibodies and drugs linked via linkers target the HIV envelope using two distinct and independent mechanisms of action. Therefore, the present invention is unique to other antibody-drug conjugates, and is useful in treating, preventing, or curing HIV.Sequence Listing SEQ ID NO: 1 SEQ ID NO: 2 SEQ ID NO: 3 SEQ ID NO: 4 SEQ ID NO: 5 SEQ ID NO: 6 SEQ ID NO: 7 SEQ ID NO: 8 SEQ ID NO: 9 SEQ ID NO: 10 SEQ ID NO: 11 SEQ ID NO: 12 SEQ ID NO: 13 SEQ ID NO: 14 SEQ ID NO: 15 SEQ ID NO: 16 SEQ ID NO: 17 SEQ ID NO: 18 SEQ ID NO: 19 SEQ ID NO: 20 SEQ ID NO: 21 SEQ ID NO: 22 SEQ ID NO: 23 SEQ ID NO: 24 SEQ ID NO: 25 SEQ ID NO: 26 SEQ ID NO: 27

Figure 1 illustrates the size-exclusion chromatography ( SEC-HPLC ) analysis of the broad-spectrum neutralizing antibody VRC01. Figure 2 illustrates the sodium dodecyl sulfate polyacrylamide gel electrophoresis ( SDS-PAGE ) of the broad-spectrum neutralizing antibody VRC01. 3A and 3B illustrate antibodies of the present invention - drug conjugate structure of; Figures 4A and 4B illustrate an antibody of the present invention - drug conjugate structure of; and FIGS. 5A and 5B described antibody of the invention - a drug binding substance of Figure 6 illustrates the structure of the drug-linker for antibody-drug conjugates; Figure 7 illustrates the structure of the drug for antibody-drug conjugates; Figure 8 illustrates the drug-linker for antibody-drug conjugates; Structure; Figure 9 illustrates the structure of the drug used for the antibody-drug conjugate; and Figure 10 illustrates the structure of the gp160 attachment inhibitor-linker replacement compound.

Claims (70)

An antibody-drug conjugate of formula (I), Ab-LD (I) wherein: Ab contains a broad-spectrum neutralizing antibody with binding affinity to HIV envelope glycoprotein; L contains a covalently bound to The linker molecule of the broad-spectrum neutralizing antibody; and D includes one or more drugs covalently bonded to the linker molecule, and the one or more drugs can bind to the HIV envelope glycoprotein. The antibody-drug conjugate of claim 1, wherein the broad-spectrum neutralizing antibody binds to the CD4 binding site. The antibody-drug conjugate of claim 2, wherein the broad-spectrum neutralizing antibody system is selected from the group consisting of VRC01, VRC01 LS, VRC07, VRC07-523, 3BNC117, NIH45-46, PGV04, b12, CH31, and CH103 . The antibody-drug conjugate of claim 2, wherein the broad-spectrum neutralizing anti-system VRC01. The antibody-drug conjugate of claim 2, wherein the broad-spectrum neutralizing anti-system VRC01 LS. The antibody-drug conjugate of claim 2, wherein the broad-spectrum neutralizing anti-system VRC07. The antibody-drug conjugate of claim 1, wherein the broad-spectrum neutralizing antibody binds to the gp120-gp41 interface. The antibody-drug conjugate of claim 7, wherein the broad-spectrum neutralizing antibody system is selected from the group consisting of 8ANC195, 35O22, and PGT151. The antibody-drug conjugate of claim 1, wherein the broad-spectrum neutralizing antibody binds to gp41 membrane-proximal external region (MPER). The antibody-drug conjugate of claim 9, wherein the broad-spectrum neutralizing anti-system is selected from the group consisting of 4E10, 10E8, 2F5, Z13e1. The antibody-drug conjugate of claim 10, wherein the broad-spectrum neutralizing anti-system 10E8. The antibody-drug conjugate of claim 1, wherein the linker molecule is an uncleavable linker. The antibody-drug conjugate of claim 12, wherein the uncleavable linker is presented in an antibody-drug conjugate selected from the group consisting of . The antibody-drug conjugate of claim 1, wherein the one or more drugs are attachment inhibitors. The antibody-drug conjugate of claim 1, wherein the one or more drugs are selected from the group consisting of: . The antibody-drug conjugate of claim 1, wherein the one or more drugs are compounds of the formula: . The antibody-drug conjugate of claim 1, wherein the one or more drugs are the following peptides: Ac-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn -Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-GluLeu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH ₂ . An antibody-drug conjugate of formula (I), (I) Ab- [LD _n ] _x where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a covalently bound to the broad-spectrum neutralizing anti-HIV antibody Linker molecule; D contains one or more drugs including HIV therapeutic compounds covalently bonded to the linker molecule L, wherein the one or more broad-spectrum neutralizing anti-HIV antibodies Ab specifically bind to HIV envelope glycoproteins And the one or more drugs D specifically bind to HIV envelope glycoprotein; n is selected from 1 to 4; and x is selected from 1 to 12. The antibody-drug conjugate of claim 18, wherein the broad-spectrum neutralizing antibody Ab binds to an HIV envelope glycoprotein selected from the group consisting of gp160, gp120, and gp41. The antibody-drug conjugate of claim 18, wherein the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein gp120. The antibody-drug conjugate of claim 18, wherein the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein gp41. The antibody-drug conjugate of claim 18, wherein the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein at the gp120 / gp41 interface. The antibody-drug conjugate of claim 18, wherein the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein gp120. The antibody-drug conjugate of claim 18, wherein the broad-spectrum neutralizing antibody Ab binds to the HIV envelope glycoprotein at the CD4-binding site. The antibody-drug conjugate of claim 18, wherein the broad-spectrum neutralizing antibody binds to gp41 near the membrane outer region (MPER). The antibody-drug conjugate of claims 1 to 24, wherein the broad-spectrum neutralizing antibody Ab is selected from the group consisting of: 2G12, 2F5, 3BC176, 3BNC60, 3BNC117, 4E10, 8ANC131, 8ANC195, 10E8, 10-1074 , 12A12, 35O22, b12, B2530, CH01-04, CH103, CH31, HJ16, M66.6, N6, N6-LS, NIH45-46, PG9, PG16, PGDM1400, PGT121, PGT128, PGT135, PGT141-PGT145, PGT151 , PGV04, VRC01, VRC01-LS, VRC07, VRC07-523, VRC07-LS and Z13. The antibody-drug conjugate of claim 19, wherein the broad-spectrum neutralizing antibody Ab is selected from the group consisting of: VRC01, VRC01-LS, VRC07, VRC07-523, VRC07-LS, 3BNC117, NIH45-46, PGV04 , B12, CH31, CH103, N6 and N6-LS. The antibody-drug conjugate of claim 19, wherein the broad-spectrum neutralizing anti-system VRC01. The antibody-drug conjugate of claim 19, wherein the broad-spectrum neutralizing anti-system VRC01-LS. The antibody-drug conjugate of claim 19, wherein the broad-spectrum neutralizing anti-system VRC07. The antibody-drug conjugate of claim 26, wherein the broad-spectrum neutralizing antibody system is selected from the group consisting of 8ANC195, 35O22, and PGT151. The antibody-drug conjugate of claim 26, wherein the broad-spectrum neutralizing antibody system is selected from the group consisting of 4E10, 10E8, 2F5, Z13e1. The antibody-drug conjugate of claim 26, wherein the broad-spectrum neutralizing anti-system N6. The antibody-drug conjugate of claim 28, wherein the broad-spectrum neutralizing antibody comprises the following 6 CDRs: CDRH1 (SEQ ID NO: 3), CDRH2 (SEQ ID NO: 4), CDRH3 (SEQ ID NO: 5) , CDRL1 (SEQ ID NO: 6), CDRL2 (SEQ ID NO: 7) and CDRL3 (SEQ ID NO: 8). The antibody-drug conjugate of claim 28, wherein the broad-spectrum neutralizing antibody comprises a heavy chain having at least 90% sequence identity with SEQ ID NO: 9 and a sequence having at least 90% sequence identity with SEQ ID NO: 10 Light chain. The antibody-drug conjugate of claim 28, wherein the broad-spectrum neutralizing antibody comprises the heavy chain variable region of SEQ ID NO: 9 and the light chain variable region of SEQ ID NO: 10. The antibody-drug conjugate of any one of claims 28 and 34 to 36, wherein the broad-spectrum neutralizing antibody comprises a leucine residue at position 428 of the heavy chain and a position 434 of the heavy chain Serine residues. The antibody-drug conjugate of claim 28, wherein the broad-spectrum neutralizing antibody comprises the heavy chain of SEQ ID NO: 11, optionally including the light chain of SEQ ID NO: 13. The antibody-drug conjugate of claim 33, wherein the broad-spectrum neutralizing antibody comprises the following 6 CDRs: CDRH1 (SEQ ID NO: 14), CDRH2 (SEQ ID NO: 15), CDRH3 (SEQ ID NO: 16) , CDRL1 (SEQ ID NO: 17), CDRL2 (SEQ ID NO: 18) and CDRL3 (SEQ ID NO: 19). The antibody-drug conjugate of claim 39, wherein the broad-spectrum neutralizing antibody comprises a heavy chain having at least 90% sequence identity with SEQ ID NO: 20 and a sequence having at least 90% sequence identity with SEQ ID NO: 21 Light chain. The antibody-drug conjugate of claim 39, wherein the broad-spectrum neutralizing antibody comprises the heavy chain variable region of SEQ ID NO: 20 and the light chain variable region of SEQ ID NO: 21. The antibody-drug conjugate of claim 33, wherein the broad-spectrum neutralizing antibody comprises a leucine residue at position 428 of the heavy chain and a serine residue at position 434 of the heavy chain. The antibody-drug conjugate of any one of claims 18 to 25, 27 to 30, 34 to 36 and 38, wherein the linker molecule is an uncleavable linker. The antibody-drug conjugate of claim 43, wherein the uncleavable linker is selected from the group consisting of: . The antibody-drug conjugate of claim 43, wherein the linker is selected from the group consisting of: , , and . The antibody-drug conjugate of claim 18, wherein the drug D specifically binds to an HIV envelope glycoprotein selected from the group consisting of gp160, gp120, and gp41. The antibody-drug conjugate of claim 18, wherein the drug D is an attachment inhibitor. The antibody-drug conjugate of claim 47, wherein the attachment inhibitor is a gp120 attachment inhibitor, a gp160 attachment inhibitor, or a gp41 attachment inhibitor. The antibody-drug conjugate of claim 47, wherein the attachment inhibitor is a gp120 attachment inhibitor or a gp160 attachment inhibitor. The antibody-drug conjugate of claim 18, wherein the drug D is a compound of the formula: . The antibody-drug conjugate of claim 18, wherein the drug D is a compound of the formula: . The antibody-drug conjugate of claim 18, wherein the drug D is a peptide that binds to CD4. The antibody-drug conjugate of claim 52, wherein the one or more drugs are peptides comprising the amino acid sequence of SEQ ID NO: 2. The antibody-drug conjugate of claim 18, wherein the drug D and linker L have the following structure: . The antibody-drug conjugate of claim 18, wherein the drug D has formula A: Wherein: X and Y are independently selected from the group consisting of: H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halo, pendant (oxo), haloalkyl , Dihaloalkyl, trihaloalkyl, haloalkoxy, dihaloalkoxy, trihaloalkoxy, hydroxyl, amine, amide and (C ₁ -C ₆ ) alkyl- (C = O ); R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from H or (C ₁ -C ₆ ) alkyl; m is in the range of 0 to 5; n is in the range of 0 to 5; r In the range of 1 to 6; p in the range of 1 to 6; and q in the range of 1 to 6. The antibody-drug conjugate of claim 55, wherein: X is selected from Cl and F; Y is H; m is 2; n is 1; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently H; r is in the range of 1 to 4; p is in the range of 1 to 4; and q is in the range of 1 to 4. An antibody drug conjugate selected from the group consisting of: , , , Where t is in the range of 1 to 12. An antibody-drug conjugate of formula (I), (I) Ab- [LD _n ] _x where: Ab contains a broad-spectrum neutralizing anti-HIV antibody; L contains a covalently bound to the broad-spectrum neutralizing anti-HIV antibody Linker molecule; D contains one or more drugs including HIV therapeutic compounds covalently bonded to the linker molecule L, wherein the one or more broad-spectrum neutralizing anti-HIV antibodies Ab specifically bind to HIV envelope glycoproteins And the one or more drugs D specifically bind to the HIV envelope glycoprotein; n is selected from 1 to 4; x is selected from 1 to 12, wherein the antibody-drug conjugate comprises (1) a covalent bond to the first connection The first drug D of the daughter molecule L, the first linker molecule L is covalently bonded to the broad-spectrum neutralizing antibody; and (2) the second drug D is covalently bonded to the second linker molecule L, the The second linker molecule L is covalently bonded to the broad-spectrum neutralizing antibody. The antibody-drug conjugate of claim 58, wherein the first drug D is the same as the second drug D. The antibody-drug conjugate of claim 58, wherein the first drug D is different from the second drug D. The antibody-drug conjugate of claim 58, wherein the two drugs are selected from the group consisting of gp120 attachment inhibitors, gp160 attachment inhibitors, and combinations thereof. The antibody-drug conjugate according to claim 18, wherein the antibody-drug conjugate comprises one or more peptides fused to the C-terminus of the heavy chain and / or light chain and the linker is 1-50 in length Amino acid. The antibody-drug conjugate of any one of claims 1 to 25, 27 to 30, 34 to 36, 38, and 46 to 62, which is used as a medicament. The antibody-drug conjugate of any one of claims 1 to 25, 27 to 30, 34 to 36, 38, and 46 to 62, which is used to treat HIV infection. A pharmaceutical composition comprising the antibody-drug conjugate according to any one of claims 1 to 62, and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 65, which contains one or more other pharmaceutical agents. The pharmaceutical composition of claim 65, which comprises one or more other HIV therapeutic agents. The pharmaceutical composition according to any one of claims 65 to 67, which is used as a medicament. The pharmaceutical composition according to any one of claims 65 to 67, which is used to treat HIV infection. Use of an antibody-drug conjugate according to any one of claims 1 to 62 or a pharmaceutical composition according to any one of claims 65 to 67 for the manufacture, treatment, cure or prevention of HIV infection in an individual Pharmacy.